HETEROARYL LINKED QUINOLINYL MODULATORS OF RORyt

ABSTRACT

The present invention comprises compounds of Formula I. 
     
       
         
         
             
             
         
       
     
     wherein:
 
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  R 8 , and R 9  are defined in the specification.
 
     The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim  1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/053,736, filed on Oct. 15, 2013, which is incorporated herein byreference.

FIELD OF THE INVENTION

The invention is directed to substituted quinoline compounds, which aremodulators of the nuclear receptor RORγt, pharmaceutical compositions,and methods for use thereof. More particularly, the RORγt modulators areuseful for preventing, treating or ameliorating an RORγt mediatedinflammatory syndrome, disorder or disease.

BACKGROUND OF THE INVENTION

Retinoic acid-related nuclear receptor gamma t (RORγt) is a nuclearreceptor, exclusively expressed in cells of the immune system, and a keytranscription factor driving Th17 cell differentiation. Th17 cells are asubset of CD4⁺ T cells, expressing CCR6 on their surface to mediatetheir migration to sites of inflammation, and dependent on IL-23stimulation, through the IL-23 receptor, for their maintenance andexpansion. Th17 cells produce several proinflammatory cytokinesincluding IL-17A, IL-17F, IL-21, and IL-22 (Korn, T., E. Bettelli, etal. (2009). “IL-17 and Th17 Cells.” Annu Rev Immunol 27: 485-517.),which stimulate tissue cells to produce a panel of inflammatorychemokines, cytokines and metalloproteases, and promote recruitment ofgranulocytes (Kolls, J. K. and A. Linden (2004). “Interleukin-17 familymembers and inflammation.” Immunity 21(4): 467-76; Stamp, L. K., M. J.James, et al. (2004). “Interleukin-17: the missing link between T-cellaccumulation and effector cell actions in rheumatoid arthritis” ImmunolCell Biol 82(1): 1-9). Th17 cells have been shown to be the majorpathogenic population in several models of autoimmune inflammation,including collagen-induced arthritis (CIA) and experimental autoimmuneencephalomyelitis (EAE) (Dong, C. (2006). “Diversification ofT-helper-cell lineages: finding the family root of IL-17-producingcells.” Nat Rev Immunol 6(4): 329-33; McKenzie, B. S., R. A. Kastelein,et al. (2006). “Understanding the IL-23-IL-17 immune pathway.” TrendsImmunol 27(1): 17-23.). RORγt-deficient mice are healthy and reproducenormally, but have shown impaired Th17 cell differentiation in vitro, asignificantly reduced Th17 cell population in vivo, and decreasedsusceptibility to EAE (Ivanov, II, B. S. McKenzie, et al. (2006). “Theorphan nuclear receptor RORgammat directs the differentiation program ofproinflammatory IL-17+ T helper cells.” Cell 126(6): 1121-33.). Micedeficient for IL-23, a cytokine required for Th17 cell survival, fail toproduce Th17 cells and are resistant to EAE, CIA, and inflammatory boweldisease (IBD) (Cua, D. J., J. Sherlock, et al. (2003). “Interleukin-23rather than interleukin-12 is the critical cytokine for autoimmuneinflammation of the brain.” Nature 421(6924): 744-8.; Langrish, C. L.,Y. Chen, et al. (2005). “IL-23 drives a pathogenic T cell populationthat induces autoimmune inflammation.” J Exp Med 201(2): 233-40; Yen,D., J. Cheung, et al. (2006). “IL-23 is essential for T cell-mediatedcolitis and promotes inflammation via IL-17 and IL-6.” J Clin Invest116(5): 1310-6.). Consistent with these findings, an anti-IL23-specificmonoclonal antibody blocks development of psoriasis-like inflammation ina murine disease model (Tonel, G., C. Conrad, et al. “Cutting edge: Acritical functional role for IL-23 in psoriasis.” J Immunol 185(10):5688-91).

In humans, a number of observations support the role of the IL-23/Th17pathway in the pathogenesis of inflammatory diseases. IL-17, the keycytokine produced by Th17 cells, is expressed at elevated levels in avariety of allergic and autoimmune diseases (Barczyk, A., W. Pierzchala,et al. (2003). “Interleukin-17 in sputum correlates with airwayhyperresponsiveness to methacholine.” Respir Med 97(6): 726-33.; Fujino,S., A. Andoh, et al. (2003). “Increased expression of interleukin 17 ininflammatory bowel disease.” Gut 52(1): 65-70.; Lock, C., G. Hermans, etal. (2002). “Gene-microarray analysis of multiple sclerosis lesionsyields new targets validated in autoimmune encephalomyelitis.” Nat Med8(5): 500-8.; Krueger, J. G., S. Fretzin, et al. “IL-17A is essentialfor cell activation and inflammatory gene circuits in subjects withpsoriasis.” J Allergy Clin Immunol 130(1): 145-154 e9.). Furthermore,human genetic studies have shown association of polymorphisms in thegenes for Th17 cell-surface receptors, IL-23R and CCR6, withsusceptibility to IBD, multiple sclerosis (MS), rheumatoid arthritis(RA) and psoriasis (Gazouli, M., I. Pachoula, et al. “NOD2/CARD15,ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn'sdisease.” World J Gastroenterol 16(14): 1753-8., Nunez, C., B. Dema, etal. (2008). “IL23R: a susceptibility locus for celiac disease andmultiple sclerosis?” Genes Immun 9(4): 289-93.; Bowes, J. and A. Barton“The genetics of psoriatic arthritis: lessons from genome-wideassociation studies.” Discov Med 10(52): 177-83; Kochi, Y., Y. Okada, etal. “A regulatory variant in CCR6 is associated with rheumatoidarthritis susceptibility.” Nat Genet 42(6): 515-9.).

Ustekinumab (Stelara®), an anti-p40 monoclonal antibody blocking bothIL-12 and IL-23, is approved for the treatment of adult patients (18years or older), with moderate to severe plaque psoriasis, who arecandidates for phototherapy or systemic therapy. Currently, monoclonalantibodies specifically targeting only IL-23, to more selectivelyinhibit the Th17 subset, are also in clinical development for psoriasis(Garber K. (2011). “Psoriasis: from bed to bench and back” Nat Biotech29, 563-566), further implicating the important role of the IL-23- andRORγt-driven Th17 pathway in this disease. Results from recent phase IIclinical studies strongly support this hypothesis, as anti-IL-17receptor and anti-IL-17 therapeutic antibodies both demonstrated highlevels of efficacy in patients with chronic psoriasis (Papp, K. A.,“Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.” NEngl J Med 2012 366(13): 1181-9.; Leonardi, C., R. Matheson, et al.“Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaquepsoriasis.” N Engl J Med 366(13): 1190-9.). Anti-IL-17 antibodies havealso demonstrated clinically relevant responses in early trials in RAand uveitis (Hueber, W., Patel, D. D., Dryja, T., Wright, A. M.,Koroleva, I., Bruin, G., Antoni, C., Draelos, Z., Gold, M. H., Durez,P., Tak, P. P., Gomez-Reino, J. J., Foster, C. S., Kim, R. Y., Samson,C. M., Falk, N. S., Chu, D. S., Callanan, D., Nguyen, Q. D., Rose, K.,Haider, A., Di Padova, F. (2010) Effects of AIN457, a fully humanantibody to interleukin-17A, on psoriasis, rheumatoid arthritis, anduveitis. Sci Transl Med 2, 5272.).

All the above evidence supports inhibition of the Th17 pathway bymodulating RORγt activity as an effective strategy for the treatment ofimmune-mediated inflammatory diseases.

SUMMARY OF THE INVENTION

The present invention comprises compounds of Formula I.

wherein:

-   -   R¹ is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,        thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl,        pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl,        isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein        said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl,        thiophenyl, benzoxazolyl, and pyrazolyl are optionally        substituted with SO₂CH₃, C(O)CH₃, C(O)NH₂, CH₃, CH₂CH₃, CF₃, Cl,        F, —CN, OCH₃, N(CH₃)₂, —(CH₂)₃OCH₃, SCH₃, OH, CO₂H, CO₂C(CH₃)₃,        or OCH₂OCH₃; and optionally substituted with up to two        additional substituents independently selected from the group        consisting of Cl, OCH₃, and CH₃; and wherein said triazolyl,        oxazolyl, isoxazolyl, and thiazolyl are optionally substituted        with one or two CH₃ groups; and wherein said azetidinyl is        optionally substituted with CO₂C(CH₃)₃, C(O)NH₂, CH₃, SO₂CH₃, or        C(O)CH₃;    -   R² is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide,        1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl,        oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl,        N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl,        N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, N-acetyl        piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl,        N—C₍₁₋₂₎alkyl-piperidinyl, thiazol-5-yl,        1-(3-methoxypropyl)-imidazol-5-yl, or 1-C₍₁₋₂₎alkyl        imidazol-5-yl; wherein said 1-C₍₁₋₂₎alkyl imidazol-5-yl is        optionally substituted with up to two additional CH₃ groups, or        one substituent selected from the group consisting of SCH₃, and        Cl; and said pyridyl, and pyridyl-N-oxide are optionally        substituted with up to two substituents independently selected        from the group consisting of C(O)NH₂, —CN, OCH₃, CF₃, Cl, and        CH₃; and said thiazol-5-yl, oxazolyl, and isoxazolyl are        optionally substituted with up to two CH₃ groups; and said        1-methyl pyrazol-4-yl is optionally substituted with up to two        additional CH₃ groups;    -   R³ is H, OH, OCH₃, NHCH₃, N(CH₃)₂ or NH₂;    -   R⁴ is H, or F;    -   R⁵ is H, Cl, —CN, CF₃, SCH₃, OC₍₁₋₃₎alkyl, OH, C₍₁₋₄₎alkyl,        N(CH₃)OCH₃, NH(C₍₁₋₂₎alkyl), N(C₍₁₋₂₎alkyl)₂, NH-cyclopropyl,        OCHF₂, 4-hydroxy-piperidinyl, azetidin-1-yl, or fur-2-yl;    -   R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl,        —N(CO₂C(CH₃)₃)phenyl, —O-pyridyl, —NHpyridyl,        —N(C₍₁₋₃₎alkyl)pyridyl, or —N(CO₂C(CH₃)₃)pyridyl wherein said        phenyl portions thereof or said pyridyl portions thereof are        optionally substituted with OCF₃, SO₂CH₃, CF₃, CHF₂,        imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, CH₃, OCH₃, Cl,        F, or —CN;    -   R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OCH₂CF₃, OCH₂CH₂OCH₃, CF₃, SCH₃,        SO₂CH₃, OCHF₂, NA¹A², C(O)NHCH₃, N(CH₃)CH₂CH₂NA¹A²,        OCH₂CH₂NA¹A², OC₍₁₋₃₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl,        imidazol-2-yl, fur-2-yl, pyrazol-4-yl, pyrid-3-yl, or        pyrimidin-5-yl; thiophen-3-yl, 1-methyl-indazol-5-yl,        1-methyl-indazol-6-yl, phenyl, or

wherein said imidazolyl or pyrazolyl can be optionally substituted witha CH₃ group;

-   -   A¹ is H or C₍₁₋₄₎alkyl;    -   A² is H, C₍₁₋₄₎alkyl, cyclopropyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl,        C₍₁₋₄₎alkylOH, C(O)C₍₁₋₂₎alkyl, or OCH₃; or A¹ and A² may be        taken together with their attached nitrogen to form a ring        selected from the group consisting of:

-   -   R_(a) is H, F, OC₍₁₋₃₎alkyl, or OH;    -   R_(b) is CH₃, or phenyl;    -   R⁸ is H, CH₃, OCH₃, or F;    -   R⁹ is H, or F;        and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises compounds of Formula I.

wherein:

-   -   R¹ is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,        thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl,        pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl,        isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein        said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl,        thiophenyl, benzoxazolyl, and pyrazolyl are optionally        substituted with SO₂CH₃, C(O)CH₃, C(O)NH₂, CH₃, CH₂CH₃, CF₃, Cl,        F, —CN, OCH₃, N(CH₃)₂, —(CH₂)₃OCH₃, SCH₃, OH, CO₂H, CO₂C(CH₃)₃,        or OCH₂OCH₃; and optionally substituted with up to two        additional substituents independently selected from the group        consisting of Cl, OCH₃, and CH₃; and wherein said triazolyl,        oxazolyl, isoxazolyl, and thiazolyl are optionally substituted        with one or two CH₃ groups; and wherein said azetidinyl is        optionally substituted with CO₂C(CH₃)₃, C(O)NH₂, CH₃, SO₂CH₃, or        C(O)CH₃;    -   R² is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide,        1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl,        oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl,        N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl,        N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, N-acetyl        piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl,        N—C₍₁₋₂₎alkyl-piperidinyl, thiazol-5-yl,        1-(3-methoxypropyl)-imidazol-5-yl, or 1-C₍₁₋₂₎alkyl        imidazol-5-yl (including 1-methyl imidazol-5-yl); wherein said        1-C₍₁₋₂₎alkyl imidazol-5-yl is optionally substituted with up to        two additional CH₃ groups, or one substituent selected from the        group consisting of SCH₃, and Cl; and said pyridyl, and        pyridyl-N-oxide are optionally substituted with up to two        substituents independently selected from the group consisting of        C(O)NH₂, —CN, OCH₃, CF₃, Cl, and CH₃; and said thiazol-5-yl,        oxazolyl, and isoxazolyl are optionally substituted with up to        two CH₃ groups; and said 1-methyl pyrazol-4-yl is optionally        substituted with up to two additional CH₃ groups;    -   R³ is H, OH, OCH₃, NHCH₃, N(CH₃)₂, or NH₂;    -   R⁴ is H, or F;    -   R⁵ is H, Cl, —CN, CF₃, SCH₃, OC₍₁₋₃₎alkyl, OH, C₍₁₋₄₎alkyl,        N(CH₃)OCH₃, NH(C₍₁₋₂₎alkyl), N(C₍₁₋₂₎alkyl)₂, NH-cyclopropyl,        OCHF₂, 4-hydroxy-piperidinyl, azetidin-1-yl, or fur-2-yl;    -   R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl,        —N(CO₂C(CH₃)₃)phenyl, —O-pyridyl, —NHpyridyl,        —N(C₍₁₋₃₎alkyl)pyridyl, or —N(CO₂C(CH₃)₃)pyridyl wherein said        phenyl portions thereof or said pyridyl portions thereof are        optionally substituted with OCF₃, SO₂CH₃, CF₃, CHF₂,        imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, CH₃, OCH₃, Cl,        F, or —CN;    -   R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OCH₂CF₃, OCH₂CH₂OCH₃, CF₃, SCH₃,        SO₂CH₃, OCHF₂, NA¹A², C(O)NHCH₃, N(CH₃)CH₂CH₂NA¹A²,        OCH₂CH₂NA¹A², OC₍₁₋₃₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl,        imidazol-2-yl, fur-2-yl, pyrazol-4-yl, pyrid-3-yl, or        pyrimidin-5-yl; thiophen-3-yl, 1-methyl-indazol-5-yl,        1-methyl-indazol-6-yl, phenyl, or

wherein said imidazolyl or pyrazolyl can be optionally substituted witha CH₃ group;

-   -   A¹ is H or C₍₁₋₄₎alkyl (including CH₂CH₃);    -   A² is H, C₍₁₋₄₎alkyl (including CH₂CH₃), cyclopropyl,        C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH, C(O)C₍₁₋₂₎alkyl, or        OCH₃; or A¹ and A² may be taken together with their attached        nitrogen to form a ring selected from the group consisting of:

-   -   R_(a) is H, F, OC₍₁₋₃₎alkyl, or OH;    -   R_(b) is CH₃, or phenyl;    -   R⁸ is H, CH₃, OCH₃, or F;    -   R⁹ is H, or F;        and pharmaceutically acceptable salts thereof.

In another embodiment of the invention:

-   -   R¹ is 6-trifluoromethyl pyrid-3-yl, pyrid-2-yl, 4-chlorophenyl,        or 3-chlorophenyl;    -   R² is 1-methyl imidazol-5-yl, or pyrid-3-yl;    -   R³ is OH;    -   R⁴ is H;    -   R⁵ is Cl, or —CN;    -   R⁶ is —O-phenyl, or —N(CO₂C(CH₃)₃)phenyl, wherein said —O-phenyl        is optionally substituted with —CN, or Cl;    -   R⁷ is Cl, NA¹A²;    -   A¹ is CH₂CH₃;    -   A² is CH₂CH₃; or A¹ and A² may be taken together with their        attached nitrogen to form a ring selected from the group        consisting of:

and pharmaceutically acceptable salts thereof.

Another embodiment of the invention is a compound selected from thegroup consisting of:

and pharmaceutically acceptable salts thereof.

Another embodiment of the invention comprises a compound of Formula Iand a pharmaceutically acceptable carrier.

The present invention also provides a method for preventing, treating orameliorating an RORγt mediated inflammatory syndrome, disorder ordisease comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of preventing, treating orameliorating a syndrome, disorder or disease, wherein said syndrome,disorder or disease is selected from the group consisting of: ophthalmicdisorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis,psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn'sDisease, ulcerative colitis, ankylosing spondylitis, nephritis, organallograft rejection, fibroid lung, systic fibrosis, renal insufficiency,diabetes and diabetic complications, diabetic nephropathy, diabeticretinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis,chronic obstructive pulmonary disease, sarcoidosis, invasivestaphylococcia, inflammation after cataract surgery, allergic rhinitis,allergic conjunctivitis, chronic urticaria, systemic lupuserythematosus, asthma, allergic asthma, steroid resistant asthma,neutrophilic asthma, periodontal diseases, periodonitis, gingivitis, gumdisease, diastolic cardiomyopathies, cardiac infarction, myocarditis,chronic heart failure, angiostenosis, restenosis, reperfusion disorders,glomerulonephritis, solid tumors and cancers, chronic lymphocyticleukemia, chronic myelocytic leukemia, multiple myeloma, malignantmyeloma, Hodgkin's disease, and carcinomas of the bladder, breast,cervix, colon, lung, prostate, or stomach comprising administering to asubject in need thereof an effective amount of a compound of Formula Ior a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis,ankylosing spondylitis, Crohn's disease, and ulcerative colitis.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis,ankylosing spondylitis, Crohn's disease, and ulcerative colitiscomprising administering to a subject in need thereof an effectiveamount of a compound of Formula I or a form, composition or medicamentthereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: inflammatory boweldiseases, rheumatoid arthritis, psoriasis, chronic obstructive pulmonarydisorder, psoriatic arthritis, ankylosing spondylitis, neutrophilicasthma, steroid resistant asthma, multiple sclerosis, and systemic lupuserythematosus comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,and psoriasis comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, in a subject in need thereof comprisingadministering to the subject an effective amount of the compound ofFormula I or composition or medicament thereof in a combination therapywith one or more anti-inflammatory agents, or immunosuppressive agents,wherein said syndrome, disorder or disease is selected from the groupconsisting of: rheumatoid arthritis, and psoriasis.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is rheumatoid arthritis, comprising administering to a subjectin need thereof an effective amount of a compound of Formula I or aform, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is psoriasis comprising administering to a subject in needthereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is chronic obstructive pulmonary disorder comprisingadministering to a subject in need thereof an effective amount of acompound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is psoriatic arthritis comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is ankylosing spondylitis comprising administering to a subjectin need thereof an effective amount of a compound of Formula I or aform, composition or medicament thereof.

The present invention provides a method of treating or ameliorating aninflammatory bowel disease, wherein said inflammatory bowel disease isCrohn's disease comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating aninflammatory bowel diseases, wherein said inflammatory bowel disease isulcerative colitis comprising administering to a subject in need thereofan effective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is neutrophilic asthma comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is steroid resistant asthma comprising administering to asubject in need thereof an effective amount of a compound of Formula Ior a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is multiple sclerosis comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is systemic lupus erythematosus comprising administering to asubject in need thereof an effective amount of a compound of Formula Ior a form, composition or medicament thereof.

The invention also relates to methods of modulating RORγt activity in amammal by administration of an effective amount of at least one compoundof Formula I.

DEFINITIONS

The term “administering” with respect to the methods of the invention,means a method for therapeutically or prophylactically preventing,treating or ameliorating a syndrome, disorder or disease as describedherein by using a compound of Formula I or a form, composition ormedicament thereof. Such methods include administering an effectiveamount of said compound, compound form, composition or medicament atdifferent times during the course of a therapy or concurrently in acombination form. The methods of the invention are to be understood asembracing all known therapeutic treatment regimens.

The term “subject” refers to a patient, which may be animal, typically amammal, typically a human, which has been the object of treatment,observation or experiment and is at risk of (or susceptible to)developing a syndrome, disorder or disease that is associated withabberant RORγt expression or RORγt overexpression, or a patient with aninflammatory condition that accompanies syndromes, disorders or diseasesassociated with abberant RORγt expression or RORγt overexpression.

The term “effective amount” means that amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein a tissue system, animal or human, that is being sought by aresearcher, veterinarian, medical doctor, or other clinician, whichincludes preventing, treating or ameliorating the symptoms of asyndrome, disorder or disease being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

The term “alkyl” refers to both linear and branched chain radicals of upto 12 carbon atoms, preferably up to 6 carbon atoms, unless otherwiseindicated, and includes, but is not limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl and dodecyl. Any alkyl group may be optionally substituted withone OCH₃, one OH, or up to two fluorine atoms.

The term “C_((a-b))” (where a and b are integers referring to adesignated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl,alkoxy or cycloalkyl radical or to the alkyl portion of a radical inwhich alkyl appears as the prefix root containing from a to b carbonatoms inclusive. For example, C₍₁₋₄₎ denotes a radical containing 1, 2,3 or 4 carbon atoms.

The term “cycloalkyl” refers to a saturated or partially unsaturatedmonocyclic or bicyclic hydrocarbon ring radical derived by the removalof one hydrogen atom from a single ring carbon atom. Typical cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. Additionalexamples include C₍₃₋₆₎cycloalkyl, C₍₅₋₈₎cycloalkyl,decahydronaphthalenyl, and 2,3,4,5,6,7-hexahydro-1H-indenyl. Anycycloalkyl group may be optionally substituted with one OCH₃, one OH, orup to two fluorine atoms.

As used herein, the term “thiophenyl” is intended to describe theradical formed by removing a hydrogen atom from the molecule with thestructure:

Pharmaceutically Acceptable Salts

Pharmaceutically acceptable acidic/anionic salts include, and are notlimited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate,bromide, calcium edetate, camsylate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,tannate, tartrate, teoclate, tosylate and triethiodide. Organic orinorganic acids also include, and are not limited to, hydriodic,perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic,hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic,cyclohexanesulfamic, saccharinic or trifluoroacetic acid.

Pharmaceutically acceptable basic/cationic salts include, and are notlimited to aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (alsoknown as tris(hydroxymethyl)aminomethane, tromethane or “TRIS”),ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calciumhydroxide, chloroprocaine, choline, choline bicarbonate, cholinechloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium,LiOMe, L-lysine, magnesium, meglumine, NH₃, NH₄OH, N-methyl-D-glucamine,piperidine, potassium, potassium-t-butoxide, potassium hydroxide(aqueous), procaine, quinine, sodium, sodium carbonate,sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.

Methods of Use

The present invention is directed to a method for preventing, treatingor ameliorating a RORγt mediated inflammatory syndrome, disorder ordisease comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

Since RORγt is an N-terminal isoform of RORγ, it is recognized thatcompounds of the present invention which are modulators of RORγt arelikely to be modulators of RORγ as well. Therefore the mechanisticdescription “RORγt modulators” is intended to encompass RORγ modulatorsas well.

When employed as RORγt modulators, the compounds of the invention may beadministered in an effective amount within the dosage range of about 0.5mg to about 10 g, preferably between about 0.5 mg to about 5 g, insingle or divided daily doses. The dosage administered will be affectedby factors such as the route of administration, the health, weight andage of the recipient, the frequency of the treatment and the presence ofconcurrent and unrelated treatments.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for compounds of the present invention or apharmaceutical composition thereof will vary according to the desiredeffect. Therefore, optimal dosages to be administered may be readilydetermined by one skilled in the art and will vary with the particularcompound used, the mode of administration, the strength of thepreparation, and the advancement of the disease condition. In addition,factors associated with the particular subject being treated, includingsubject age, weight, diet and time of administration, will result in theneed to adjust the dose to an appropriate therapeutic level. The abovedosages are thus exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention.

The compounds of Formula I may be formulated into pharmaceuticalcompositions comprising any known pharmaceutically acceptable carriers.Exemplary carriers include, but are not limited to, any suitablesolvents, dispersion media, coatings, antibacterial and antifungalagents and isotonic agents. Exemplary excipients that may also becomponents of the formulation include fillers, binders, disintegratingagents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quaternary ammoniumsalts which are formed from inorganic or organic acids or bases.Examples of such acid addition salts include acetate, adipate, benzoate,benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride,hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate,pivalate, propionate, succinate, sulfate and tartrate. Base saltsinclude ammonium salts, alkali metal salts such as sodium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases such as dicyclohexylamino salts and salts withamino acids such as arginine. Also, the basic nitrogen-containing groupsmay be quaternized with, for example, alkyl halides.

The pharmaceutical compositions of the invention may be administered byany means that accomplish their intended purpose. Examples includeadministration by parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, buccal or ocular routes. Alternatively orconcurrently, administration may be by the oral route. Suitableformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form, for example, water-solublesalts, acidic solutions, alkaline solutions, dextrose-water solutions,isotonic carbohydrate solutions and cyclodextrin inclusion complexes.

The present invention also encompasses a method of making apharmaceutical composition comprising mixing a pharmaceuticallyacceptable carrier with any of the compounds of the present invention.Additionally, the present invention includes pharmaceutical compositionsmade by mixing a pharmaceutically acceptable carrier with any of thecompounds of the present invention.

Polymorphs and Solvates

Furthermore, the compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and as such are intended to beincluded in the scope of the invention. In addition, the compounds mayform solvates, for example with water (i.e., hydrates) or common organicsolvents. As used herein, the term “solvate” means a physicalassociation of the compounds of the present invention with one or moresolvent molecules. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances the solvate will be capable of isolation, for example when oneor more solvent molecules are incorporated in the crystal lattice of thecrystalline solid. The term “solvate” is intended to encompass bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.

It is intended that the present invention include within its scopepolymorphs and solvates of the compounds of the present invention. Thus,in the methods of treatment of the present invention, the term“administering” shall encompass the means for treating, ameliorating orpreventing a syndrome, disorder or disease described herein with thecompounds of the present invention or a polymorph or solvate thereof,which would obviously be included within the scope of the inventionalbeit not specifically disclosed.

In another embodiment, the invention relates to a compound as describedin Formula I for use as a medicament.

In another embodiment, the invention relates to the use of a compound asdescribed in Formula I for the preparation of a medicament for thetreatment of a disease associated with an elevated or aberrant RORγtactivity.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, Ed. H. Bundgaard, Elsevier, 1985.

Furthermore, it is intended that within the scope of the presentinvention, any element, in particular when mentioned in relation to acompound of Formula I, shall comprise all isotopes and isotopic mixturesof said element, either naturally occurring or synthetically produced,either with natural abundance or in an isotopically enriched form. Forexample, a reference to hydrogen includes within its scope ¹H, ²H (D),and ³H (T). Similarly, references to carbon and oxygen include withintheir scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopesmay be radioactive or non-radioactive. Radiolabelled compounds ofFormula I may comprise a radioactive isotope selected from the group of³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br.Preferably, the radioactive isotope is selected from the group of ³H,¹¹C and ¹⁸F.

Some compounds of the present invention may exist as atropisomers.Atropisomers are stereoisomers resulting from hindered rotation aboutsingle bonds where the steric strain barrier to rotation is high enoughto allow for the isolation of the conformers. It is to be understoodthat all such conformers and mixtures thereof are encompassed within thescope of the present invention.

Where the compounds according to this invention have at least onestereocenter, they may accordingly exist as enantiomers ordiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Abbreviations

Herein and throughout the application, the following abbreviations maybe used.

1, 8-ANS 1-anilinonaphthalene-8-sulfonic acid Å angstrom Ac acetyl Araryl ACN acetonitrile Boc tert-butyloxy carbonyl bs broad singlet Bubutyl n-BuLi n-butyllithium d doublet dd doublet of doublets dbadibenzylideneacetone DCM dichloromethane Dess-Martin1,1,1-tris(acetyloxy)-1,1-dihydro-1,2- periodinanebenziodoxol-3-(1H)-one DMAP dimethylaminopyridine DMFN,N-dimethylformamide DMSO dimethyl sulfoxide dppf(diphenylphosphino)ferrocene dt doublet of triplets Eaton's 7.7 wt %phosphorus pentoxide solution in Reagent methanesulfonic acid EDCIN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ESIelectrospray ionization Et ethyl Et₂O diethyl ether EtOAc ethyl acetateEtOH ethyl alcohol Et₃SiCl chlorotriethylsilane GSH glutathione HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate Hunig's base N, N-diisopropylethylamine HPLC highpressure liquid chromatography Hz hertz i-PrOH isopropyl alcohol LCMSliquid chromatography-mass spectrometry m multiplet M molar(moles/liter) Me methyl Meldrum's 2,2-dimethyl-1,3-dioxane-4,6-dioneacid MeOH methanol MHz megahertz min minutes mL mililiters MTBE methyltertiary butyl ether nm nanometers NaO^(i)Pr sodium isopropoxide NBSN-bromosuccinimide NMR nuclear magnetic resonance Ph phenyl ppm partsper million Pr propyl q quartet s singlet t triplet td triplet ofdoublets TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layerchromatography UV ultra-violet X-phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

General Schemes:

Compounds of Formula I in the present invention can be synthesized inaccordance with the general synthetic methods known to those who areskilled in the art. The following reaction schemes are only meant torepresent examples of the invention and are in no way meant to be alimit of the invention.

Scheme 1 describes the preparation of 6-haloquinoline intermediates ofFormula VI. Methyl 2-amino-5-halobenzoates II can undergo acylation withsubstituted acid chlorides III (R⁶ is substituted arylamino,heteroarylamino, aryloxy, or heteroaryloxy as described above), or canbe condensed with substituted carboxylic acids IV using EDCI and a base,to form amide intermediates. The acid chlorides III can be obtainedcommercially or prepared from the corresponding carboxylic acids usingmethods known in the art. The amide intermediates can be cyclized bytreatment with a base, such as potassium bis(trimethylsilyl)amide, toafford 6-halo-4-hydroxyquinolin-2(1H)-ones V. Heatinghydroxyquinolin-2(1H)-ones V with phosphorus oxychloride, neat or in asolvent such as acetonitrile, yields 2,4-dichloroquinolines VI.Displacement of the 2-Cl of 2,4-dichloroquinolines VI with sodiumalkoxides can be accomplished in an alcoholic solvent such as methanol,ethanol or isopropanol or at elevated temperatures in a non-polarsolvent such as toluene (Alan Osborne et. al. J. Chem. Soc. PerkinTrans. 1 (1993) 181-184 and J. Chem. Research (S), 2002, 4) to providesubstituted quinolines VI wherein R⁵ is Cl and R⁷ is Oalkyl (path 1).Additional intermediates of Formula VI where R⁷ is N(alkyl)₂ can beobtained by displacement of the 2-Cl group of 2,4-dichloroquinolines VIwith disubstituted amines, such as NHMe₂, NHEt₂, NHMeEt, or azetidine ina hot polar solvent, such as MeOH, EtOH, or DMF (path 2).

An alternative route to 6-haloquinolines VI where R⁶ is substitutedarylamino or heteroarylamino is shown in Scheme 2. 4-Haloanilines VIIcan be heated with 2,2-dimethyl-1,3-dioxan-4,6-dione (Meldrum's acid) toform 3-((4-halophenyl)amino)-3-oxopropanoic acids VIII Cyclization ofVIII in Eaton's reagent at elevated temperature then affords4-hydroxyquinolinone intermediates (Synth. Commun. 2010, 40, 732), whichcan be treated with (diacetoxyiodo)benzene and trifluoromethanesulfonicacid to yield 4-hydroxyquinolinone phenyliodoniumtrifluoromethanesulfonates IX (Org. React. 2001, 57, 327). Reaction of theseintermediates with arylamines or heteroarylamines yields substituted3-amino-4-hydroxyquinolinones X (Monatsh. Chem. 1984, 115 (2), 231),which may be heated in phosphorus oxychloride to afford2,4-dichloroquinolines VI. In cases where R⁶ is a secondary amine, theseintermediates may be further functionalized to form amides by reactionwith an acid chloride and a tertiary amine base, or to form carbamatesby reaction with a dialkyl dicarbonate, such as di-tert-butyldicarbonate, and DMAP in a polar solvent such as THF or DMF.

Scheme 3 describes the synthesis of 2- and 4-trifluoromethylquinolinesVI. Treatment of 1-halo-4-fluorobenzenes XI with lithiumdiisopropylamide at −78° C. followed by addition of ethyltrifluoroacetate gives 2-fluorophenyl-2,2,2-trifluoroethanones XII.Displacement of the 2-fluoro substituent in XII with sodium azidefollowed by reduction of the azide intermediates, for example with tin(II) chloride dihydrate, yields anilines XIII Acylation of anilines XIIIwith acid chlorides III or with carboxylic acids IV in the prescence ofa coupling agent such as EDCI and base, such as triethylamine orpotassium tert-butoxide, leads directly to cyclized quinolin-2(1H)-onesXIV. Heating 4-(trifluoromethyl)quinolin-2(1H)-ones XIV with phosphorusoxychloride in the presence of diisopropylethylamine yields6-haloquinolines VI wherein R⁵ is CF₃ and R⁷ is Cl (path 1).4-Chloro-2-(trifluoromethyl)quinolines can be prepared starting from2-aminobenzoic acids XV (path 2). Cyclization of XV with substituted1,1,1-trifluoropropan-2-ones in Eaton's reagent at elevated temperaturesyields 4-hydroxy-2-(trifluoromethyl)quinolines XVI, which upon heatingin phosphorus oxychloride yields 6-haloquinolines VI wherein R⁵ is Cland R⁷ is CF₃.

Scheme 4 illustrates methods for the preparation of 6-haloquinolineintermediates VI in which either R⁵ or R⁷ is hydrogen. Amides XVII,formed by acylation of anilines VII as previously described above, canbe cyclized to quinolines VI wherein R⁵ is H and R⁷ is Cl by formylationusing Vilsmeier-Haack conditions (POCl₃/DMF) followed by heating topromote ring cylization (path 1). 6-Haloquinolines VI where R⁵ is Cl andR⁷ is H can be prepared by the methods shown in paths 2, 3 and 4.4-Haloanilines VII can be reacted with in situ generatedmethoxymethylene Meldrum's acid to form enamines XVIII which can cyclizeby heating in the range of 250-300° C. in a non-polar high-boilingsolvent such as diphenyl ether, to provide 4-hydroxyquinolines XIX(Madrid, P. B. et al., Bioorg. Med. Chem. Lett., 2005, 15, 1015).4-Hydroxyquinolines XIX may be nitrated at the 3-position by heatingwith nitric acid in an acidic solvent, such as propionic acid, toprovide 3-nitro-4-hydroxyquinolines XX (path 3). Heating theseintermediates with POCl₃ and reduction of the nitro group, for instanceusing tin(II) chloride dihydrate, provides 3-amino-4-chloroquinolinesXXI. N-arylation or N-heteroarylation can be accomplished using aryl orheteroaryl boronic acids and a copper salt, such as Cu(OAc)₂, in thepresence of a tertiary amine base. The resulting secondary amines can befurther elaborated to 6-haloquinolines of Formula VI where is R⁵ is Cl,R⁶ is substituted arylamino or heteroarylamino, and R⁷ is H byN-alkylation or acylation with an alkyl halide or acid chloride,respectively, in the presence of a base. Alternatively,4-hydroxyquinolines XIX may be brominated at the 3-position by heatingwith N-bromosuccinamide in acetic acid to furnish3-bromo-4-hydroxyquinolines XXII (path 4). Displacement of the 3-bromosubstituent can be accomplished by heating with an aryl or heteroarylpotassium phenoxide salt in the presence of copper powder and copper (I)bromide in a polar solvent, such as DMF, as described in Collini, M. D.et al., US 20050131014. The resulting 4-hydroxyquinolines XXIII can beheated in POCl₃ to provide 6-haloquinolines VI where R⁵ is Cl, R⁶ isaryloxy or heteroaryloxy, and R⁷ is H.

Scheme 5 illustrates synthetic routes (path 1 to 6) to ketones ofFormula XXVIII In path 1, Weinreb amide XXV can be prepared from acidsXXIV by reacting with N,O-dimethylhydroxylamine hydrochloride and1,1-carbonyldiimidazole or with N,O-dimethylhydroxylamine hydrochloridein the presence of a base such as triethylamine or Hunig's base and acoupling reagent such as EDCI. The amides XXV can be further treatedwith Grignard reagents such as R²MgX (X is Br or Cl) that can beobtained commercially or preformed by treatment of R²Z withorganometallic reagents such as i-PrMgCl or EtMgCl in THF.Alternatively, Weinreb amides XXV can be obtained from acyl chloridesXXIX, which can be obtained commercially or prepared from thecorresponding carboxylic acids using methods known in the art, andN,O-dimethylhydroxylamine hydrochloride by using triethylamine orpyridine as a base. 1-Methyl-1H-imidazole can be treated with oneequivalent of n-BuLi and one equivalent of chlorotriethylsilane at −78°C. followed by an additional equivalent of n-BuLi, to which the Weinrebamides XXV can be added to yield ketones XXVIII wherein R² is imidazolyl(path 2).

In path 3, halogen-metal exchange of bromides or iodides XXVII withi-PrMgCl.LiCl or n-BuLi, followed by addition of aldehydes XXX affordsalcohols XXXI. Oxidation of XXXI with Dess-Martin periodinane or MnO₂can provide ketones XXVIII. In path 4, ketones XXVIII, where R² istriazolyl, can be prepared by treatment of 1-methyl-1H-1,2,3-triazolewith n-BuLi followed by reaction with aldehydes XXX to yield alcoholsXXXI, which could undergo oxidation with Dess-Martin periodinane orMnO₂. Path 5 exemplifies the preparation of symmetrical ketones XXVIII,wherein R¹ and R² are the same. As illustrated, an aryl or heteroarylgroup containing an acidic proton XXXIX (Y=R¹ or R²) can be deprotonatedin the presence of a strong base such as n-BuLi once solubilized in apreferred solvent such as tetrahydrofuran at temperatures between 0 and−78° C. then added in excess to ethyl methoxy(methyl)carbamate toprovide aryl ketones XXVIII wherein R¹ and R² are the same. Aryl orheteroaryl bromide or iodide XL can also be lithiated through alithium/halogen exchange with n-BuLi before adding in excess to ethylmethoxy(methyl)carbamate as previously described to provide symmetricalketones XXVIII Path 6, which employs palladium catalyzed cross-couplingof arylboronic acids XLI with acid chlorides XLII using K₃PO₄ as a baseand (Ph₃P)₂PdCl₂ as a catalyst in a high boiling non-polar solvent suchas toluene, can also be used to generate ketones XXVIII.

Scheme 6 illustrates synthetic routes leading to compounds of Formula I(paths 1 and 2). As illustrated in path 1, a mixture of the6-haloquinolines VI in an appropriate solvent such as THF can be eitherpremixed with the aryl ketones XXVIII at −78° C. followed by addition ofn-BuLi or the 6-haloquinolines VI can be pretreated with n-BuLi at −78°C. prior to the addition of the aryl ketones XXVIII to afford thetertiary alcohols of Formula I, wherein R³ is OH. In path 2,6-iodoquinolines VI can be treated with i-PrMgCl followed by addition ofketones XXVIII to yield compounds of Formula I wherein R³ is OH.

An alternative route to compounds of Formula I is shown in Scheme 7. Inpath 1, treatment of 6-haloquinolines VI with n-BuLi at −78° C. followedby addition of aldehydes XXX provides secondary alcohol quinolinesXXXII, which can be oxidized to ketones XXXIII with Dess-Martinperiodinane or MnO₂. Alternatively, ketones XXXIII may be prepared bytreatment of 6-haloquinolines VI with n-BuLi at −78° C. followed byquenching with DMF affording quinoline carboxaldehydes XXXIV. KetonesXXXIII can be obtained in a two-step process by addition of aldehydesXXXIV to a reaction mixture of aryl iodides XXXV and i-PrMgCl.LiClfollowed by oxidation with MnO₂ (path 2). Halogen-metal exchange of arylhalides (iodide or bromide) XXVII with an organometallic reagent, suchas n-BuLi, i-PrMgCl.LiCl, or EtMgCl, at an appropriate temperature, suchas −78° C. or 0° C., followed by reaction with ketones XXXIII may affordtertiary alcohol quinolines of Formula I.

Scheme 8 illustrates methods used to synthesize compounds of Formula Iwherein either the chlorine at R⁷ or at both R⁵ and R⁷ positions arereplaced with nitrogen, oxygen, sulfur or alkyl groups. In paths 1 and4, nucleophilic displacement of 2,4-dichloroquinolines I (R⁵ and R⁷ areCl) with NaO(alkyl) or NaS(alkyl), such as NaOMe, NaSMe, NaOEt, orNaO^(i)Pr, in an appropriate solvent, such as MeOH, EtOH, i-PrOH or DMFat elevated temperatures or with substituted hydroxy reagents such as2-methoxyethanol in the presence of a base like sodium hydride in anon-polar solvent such as toluene provides compounds of Formula Iwherein R⁵ is Cl and R⁷ is O(alkyl), O(CH₂)₂OCH₃ or S(alkyl) andcompounds of Formula I wherein R⁵ and R⁷ are O(alkyl) or S(alkyl).Likewise, nucleophilic displacement of 2,4-dichloroquinolines I (R⁵ andR⁷ are Cl) with primary or secondary alkyl amines, heterocyclic amines,or N,O-dimethylhydroxylamine in polar solvents such as MeOH, EtOH,Et₂NCHO, or DMF provides quinolines of Formula I (path 2) wherein R⁵ isNH(alkyl), N(alkyl)₂, N(CH₃)OCH₃, or Cl, and R⁷ is NH(alkyl), N(alkyl)₂,N(CH₃)OCH₃, NA¹A², NHC₍₂₋₃₎alkylNA¹A² or N(CH₃)C₍₂₋₄₎alkylNA¹A², whereinA¹ and A² are as defined above. Introduction of cyclic amides can beaccomplished using Buchwald palladium catalyzed coupling conditions toprovide compounds of Formula I, wherein R⁷ are rings such asazetidin-2-ones or pyrrolidin-2-ones. Replacement of chlorine atpositions 2- and 4- of quinolines I (R⁵ and R⁷ are Cl) with alkyl groupscould be carried out using Zn(alkyl)₂ in the presence of K₂CO₃ and apalladium catalyst, such as PdCl₂(dppf), to afford 2-alkyl and2,4-dialkylquinolines I (path 3).

Synthetic routes to compounds of Formula I, wherein R⁵ is Cl or CN, andR⁷ is CN or aryl, are illustrated in Scheme 9. In path 1, cyanation ofthe 2,4-dichloroquinolines I with Zn(CN)₂ in the presence of Zn (dust,<10 μm), a palladium catalyst, such as Pd₂dba₃, and a ligand, such asdppf or X-phos, at high temperatures can provide 2-CN and 2,4-diCNquinolines I. The 2,4-dichloroquinolines I can also undergo Suzukireactions with ArB(OH)₂ or ArB(OR)₂ and a palladium catalyst, such asPdCl₂(dppf), yielding compounds of Formula I wherein R⁷ is phenyl,substituted phenyl and five or six-membered ring heteroaryls such asfuran, pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, orimidazole (path 2).

As illustrated in Scheme 10, compounds of Formula I prepared in Schemes8 and 9 wherein R⁵ is a chlorine and R⁷ is not a chlorine can be furthersubstituted by treatment with alkylboronic acids or esters under Suzukireaction conditions (path 1), with sodium alkoxides (path 2), or withzinc cyanide (path 3) using conditions previously described to providecompounds of Formula I wherein R⁵ is alkyl, O(alkyl) or CN and R⁷ is asdescribed above.

In Scheme 11, tertiary alcohols I can be treated with base, such as NaH,and alkylated with MeI in DMF to provide compounds of Formula I whereinR³ is OMe.

Synthetic routes to compounds of Formula I, wherein R³ is NH₂, areillustrated in Scheme 12. Ketimines XXXVI may be prepared by Ti(OEt)₄mediated condensation of ketones XXVIII with2-methylpropane-2-sulfinamide in refluxing THF. Addition of n-BuLi tothe reaction mixture of ketimines XXXVI and 6-haloquinolines VI at −78°C. followed by cleavage of the tert-butanesulfinyl group with HCl inMeOH liberates amines I. Alternatively, compounds of Formula I, whereinR³ is OH can be treated with sodium hydride followed by addition ofacetic anhydride or acetyl chloride and stirred at room temperature overa 24 to 72 hour period to provide the intermediate acetate wherein R³ isOAc. The acetate can then be combined with a solution of ammonia inmethanol and heated at temperatures between 60 and 85° C. to providecompounds of Formula I, wherein R³ is NH₂.

As shown in Scheme 13, the quinolines of Formula I wherein R⁷ is —CN canbe hydrolyzed as described in US20080188521 by treatment with sodiumcarbonate and hydrogen peroxide to provide compounds of Formula Iwherein R⁷ is CONH₂ (path 1) or can be treated with a strong acid likeHCl to convert —CN to a carboxylic acid (path 2). Once formed the acidXXXVII can be further coupled to substituted amines using appropriatecoupling reagents such as EDCI or HATU in the presence of a base such astriethylamine or Hunig's base to provide compounds of Formula I whereinR⁷ is CONA¹A².

Synthesis of compounds of Formula I, wherein R⁷ is anaminoalkylaminomethylene or an aminoalkoxymethylene can be prepared from2-methylquinolines as shown in Scheme 14. Bromination of2-methylquinolines of Formula I can be accomplished withN-bromosuccinamide in acetic acid at elevated temperatures as describedin WO2010151740, to provide the methylbromide intermediates XXXVIIINucleophilic displacement of the bromide under basic conditions usingprocedures known in the art could afford compounds of Formula I whereinR⁷ is —CH₂N(H)C₍₂₋₃₎alkylNA¹A² or —CH₂N(CH₃)C₍₂₋₃₎alkylNA¹A² (path 1) orCH₂OC₍₂₋₃₎alkylNA¹A² (path 2) and A¹ and A² are defined above.

Compounds of Formula I wherein R¹, R² or R⁶ are pyridyl can be treatedwith m-chloroperbenzoic acid in a chlorinated solvent at ambient to 40°C. to form the pyridyl-N-oxides of Formula I.

As shown in Scheme 15, compounds of the Formula I wherein R³ is H can beprepared by treating compounds of Formula I wherein R³ is OH with anacid such as trifluoracetic acid in a solvent such as dichloromethane atroom temperature or with heating (WO2009091735).

EXAMPLES

Compounds of the present invention can be prepared by methods known tothose who are skilled in the art. The following examples are only meantto represent examples of the invention and are in no way meant to be alimit of the invention.

Intermediate 1: Step a 4-Chloro-N-methoxy-N-methylbenzamide

Pyridine (27.6 mL, 343 mmol) was added to N,O-dimethylhydroxylaminehydrochloride (16.7 g, 172 mmol) in DCM (400 mL). 4-Chlorobenzoylchloride (20 mL, 156 mmol) was then added and the mixture was stirred atroom temperature for 3 days. Solids were removed by vacuum filtrationand washed with DCM. The filtrate was washed with 1 N aqueous HClfollowed by water. The organic phase was dried (Na₂SO₄), filtered, andconcentrated, affording the crude title compound as a colorless liquidwhich was used without purification in the next step.

Intermediate 1: Step b(4-Chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone

Ethyl magnesium bromide (3.0 M in diethyl ether, 21.5 mL, 64.4 mmol) wasadded via syringe over a few minutes to a clear colorless solution of5-bromo-1-methyl-1H-imidazole (10.4 g, 64.4 mmol) in THF (100 mL) undera nitrogen atmosphere in an ice bath. A white precipitate formed duringthe addition. The mixture was removed from the ice bath and was stirredfor 20 min, then was again cooled in an ice bath before addition of4-chloro-N-methoxy-N-methylbenzamide (10.7 g, 53.6 mmol, Intermediate 1:step a). The resulting white suspension was stirred overnight at roomtemperature. The reaction was quenched by addition of saturated aqueousNH₄Cl and diluted with water. The mixture was partially concentrated toremove THF and was diluted with DCM. The mixture was acidified to pH 1with 1 N aqueous HCl, then neutralized with saturated aqueous NaHCO₃.The phases were separated and the aqueous phase was further extractedwith DCM. The organic extracts were washed with water, then were dried(Na₂SO₄), filtered, and concentrated, affording a white solid. The crudeproduct was triturated with a mixture of EtOAc:heptanes (1:1, 150 mL).The precipitated solid was collected by vacuum filtration and washedwith heptanes to afford the title compound.

Intermediate 2: Step a 2-(4-Cyanophenoxy)acetyl chloride

To a suspension of commercially available 2-(4-cyanophenoxy)acetic acid(4.0 g, 22.6 mmol) in dichloromethane (80 mL) was added oxalyl chloride(2.17 mL, 24.8 mmol). To this mixture was added N,N-dimethylformamide(30 μL) dropwise and the mixture was stirred for 2 hours during whichcessation of evolution of gas was observed. The resulting solution wasdiluted with dichloromethane (50 mL) and the solvent was removed underreduced pressure to provide the title compound as an oil which became asolid upon storing in the refrigerator.

Intermediate 2: Step b Methyl5-bromo-2-(2-(4-cyanophenoxy)acetamido)benzoate

To a solution of methyl 2-amino-5-bromobenzoate (4.0 g, 17.39 mmol) indichloromethane (60 mL) was added 2-(4-cyanophenoxy)acetyl chloride(3.74 g, 19.13 mmol, Intermediate 2: step a) to form a thick suspension.An additional 30 mL of dichloromethane was added. The reaction was thencooled to 0° C. and triethylamine (5.32 mL, 38.25 mmol) was addeddropwise. The cold bath was removed and the reaction was stirred at roomtemperature for 2 hours, then filtered to give the title compound as awhite solid. The filtrate was washed with water, followed by saturatedaqueous NH₄Cl solution. The organic layer was dried (MgSO₄), filtered,concentrated, and the residue was purified by flash columnchromatography (silica gel, 20% EtOAc-heptane) to afford more of thetitle compound.

Intermediate 2: Step c4-((6-Bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)oxy)benzonitrile

To a suspension of methyl5-bromo-2-(2-(4-cyanophenoxy)acetamido)benzoate (0.240 g, 0.617 mmol,Intermediate 2: step b) in THF (6.65 mL) at −78° C. was added potassiumbis(trimethylsilyl)amide (0.5 M in toluene, 3.66 mL, 1.83 mmol) over 1.5minutes, and the mixture was stirred for 5 minutes. The dry-ice/acetonebath was replaced with wet-ice bath and the reaction was stirred for 1.5hours. The reaction was then quenched with water and ethyl acetate wasadded. The organic layer was removed and the aqueous layer was acidifiedwith 2 N HCl (kept pH above 2). An off-white precipitate was formedwhich was filtered and the solid was dried overnight in the air and 1hour in an oven at 40° C. to give the title compound.

Intermediate 2: Step d4-((6-Bromo-2,4-dichloroquinolin-3-yl)oxy)benzonitrile

To a suspension of4-((6-bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)oxy)benzonitrile(1.8 g, 5.04 mmol, Intermediate 2: step c) in acetonitrile (10 mL) wasadded phosphorous oxychloride (2.35 mL, 25.20 mmol) and the mixture washeated to 100° C. overnight. The reaction was concentrated,dichloromethane was added and the organic layer was washed with water,dried (MgSO₄), filtered and concentrated. The residue was purified overa silica gel column with ethyl acetate/heptane to give the titlecompound.

Intermediate 34-((6-Bromo-4-chloro-2-(pyrrolidin-1-yl)quinolin-3-yl)oxy)benzonitrile

To 4-((6-bromo-2,4-dichloroquinolin-3-yl)oxy)benzonitrile (0.330 g,0.837 mmol, Intermediate 2: step d) was added N,N-dimethylformamide (3mL) and pyrrolidine (0.070 mL, 0.837 mmol), and the reaction was heatedat 60° C. for 3 hours, followed by heating to 100° C. for 2 hours. Anadditional 2 equivalents of pyrrolidine (0.140 mL, 1.675 mol) was addedand the reaction was heated overnight. The reaction was cooled, dilutedwith ethyl acetate and the organic layer was washed with water to removethe N,N-dimethylformamide. The organic layer was dried (MgSO₄), filteredand concentrated, then purified over a silica gel column with ethylacetate/heptane to afford the title compound.

Intermediate 4: Step a 6-(Trifluoromethyl)nicotinoyl chloride

To a 1 L 3-neck flask equipped with an overhead stirrer, Claisenadaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple wasadded 6-(trifluoromethyl)nicotinic acid (45.0 g, 236 mmol),dichloromethane (540 mL) and DMF (0.910 mL, 11.8 mmol) via syringe. Tothis solution was added oxalyl chloride (24.5 mL, 283 mmol) and thereaction was allowed to stir at ambient temperature overnight. Thereaction was then filtered and the clear filtrate was concentrated invacuo to afford the title compound as a brown semisolid.

Intermediate 4: Step bN-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide

To a 1 L 3-neck flask equipped with an overhead stirrer, Claisenadaptor, nitrogen bubbler, 125 mL addition funnel, and thermocouple wasadded 6-(trifluoromethyl)nicotinoyl chloride (49.3 g, 235 mmol,Intermediate 4: step a), dichloromethane (493 mL), andN,O-dimethylhydroxylamine hydrochloride (25.63 g, 258.8 mmol). After themixture was cooled to 7° C., diisopropylethylamine (90.26 mL, 517.6mmol) was added such that the addition temperature did not exceed 16° C.After the addition, the reaction was allowed to warm to roomtemperature. The reaction was then transferred to a separatory funneland the organic layer was washed with saturated aqueous NaHCO₃ (2×100mL) followed by water (100 mL) and then dried over sodium sulfate andfiltered. Removal of solvent afforded a brown oil as the title compound.

Intermediate 4: Step c(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone

To a 3 L 4-neck flask equipped with an overhead stirrer, nitrogenbubbler, and thermocouple was added 5-bromo-1-methyl-1H-imidazole (47.96g, 297.9 mmol), followed by THF (537 mL). To this room temperaturesolution was added isopropylmagnesium chloride/lithium chloride complex(246.8 mL, 320.8 mmol, 1.3 M in THF) (addition temperature maintainedbetween 16.6 and 25° C.) to afford a milky suspension and the reactionwas stirred for 60 minutes and then cooled to 5.3° C. in an ice bath. Tothis mixture was added a solution ofN-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (53.66 g, 229.1 mmol,Intermediate 4: step b) in THF (268 mL) (addition temperature between5.3 and 5.6° C.) to afford an orange mixture. After addition, thereaction was warmed to room temperature over 2 hours. After stirring atroom temperature for 18 hours, THF (200 mL) was added and the reactionwas stirred for 2 hours. The reaction was then cooled to 4° C. with anice bath and carefully quenched with 2 N aqueous HCl to pH=7, quenchingtemperature reached 12° C. The mixture was diluted with ethyl acetate(500 mL), the phases were separated, and the organic layer was washedwith brine (2×200 mL) and dried over sodium sulfate, filtered and thesolvent was removed. Hot ether was added and then filtered to give thetitle compound as a solid.

Intermediate 5: Step a Methyl 5-bromo-2-(2-phenoxyacetamido)benzoate

To a solution of commercially available methyl 2-amino-5-bromobenzoate(10.0 g, 43.5 mmol) in dichloromethane (100 mL) was added2-phenoxyacetyl chloride (6.60 mL, 47.8 mmol). The white suspensionformed was cooled to 0° C. and treated with triethylamine (13.3 mL, 95.6mmol) dropwise. The resulting solution was stirred at room temperaturefor 0.5 hours. The mixture was diluted with CH₂Cl₂ and was washed withwater and saturated aqueous NH₄Cl solution. The organic phase was dried(MgSO₄), filtered, and concentrated. The residue was purified by flashcolumn chromatography (silica gel, 7% EtOAc-heptane), to afford thetitle compound.

Intermediate 5: Step b 6-Bromo-4-hydroxy-3-phenoxyquinolin-2(1H)-one

To a solution of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (7.28 g,20.0 mmol, Intermediate 5: step a) in tetrahydrofuran (215 mL) at −78°C. was added potassium bis(trimethylsilyl)amide (0.5 M solution intoluene, 118.7 mL, 59.37 mmol) over 7 minutes. The mixture was stirredat −78° C. for 5 minutes and 0° C. for 1.5 hours. The resulting coldsolution was quenched with water. The white solid formed was completelydissolved by addition of excess water. The aqueous phase was washed oncewith EtOAc and then acidified by slow addition of 2 N aqueous HClsolution (kept pH above 2). The off-white precipitate formed wasfiltered and dried in the air overnight and at 40° C. for 1 hour toprovide the title compound.

Intermediate 5: Step c 6-Bromo-2,4-dichloro-3-phenoxyquinoline

To a suspension of 6-bromo-4-hydroxy-3-phenoxyquinolin-2(1H)-one (4.30g, 13.0 mmol, Intermediate 5: step b) in CH₃CN (30 mL) was addedphosphoryl chloride (3.60 mL, 38.8 mmol). The resulting mixture washeated at 100° C. for 16 hours. The dark suspension was cooled to roomtemperature and filtered. The solid residue was washed with cold MeOH toprovide an off-white solid. The filtrate was concentrated to one thirdof its volume, then a small amount of MeOH was added and cooled to 0° C.to provide a second batch of solid suspension. This was filtered and theresidue was washed with cold MeOH. The two batches of solid werecombined and dried under vacuum to provide the title compound.

Intermediate 5: Step d6-Bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine

A mixture of 6-bromo-2,4-dichloro-3-phenoxyquinoline (2.92 g, 7.91 mmol,Intermediate 5, step c), diethylamine (8.2 mL, 79.1 mmol) and DMF (2 mL)in a sealed tube were heated at 80° C. for 15 hours. The resultingsolution was cooled to room temperature and diluted with EtOAc. Theorganic phase was washed thoroughly with water, dried (MgSO₄), filteredand concentrated. The residue was purified by flash columnchromatography (silica gel, 5% EtOAc-heptane), affording the titlecompound.

Intermediate 6: Step a (1-Methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol

A solution of isopropylmagnesium chloride/lithium chloride complex (1.3M in THF, 19.5 mL, 25.35 mmol) was added dropwise by syringe to asolution of 5-bromo-1-methyl-1H-imidazole (4.12 g, 25.58 mmol) in dryTHF (130 mL) at 0° C. After 15 minutes, the Grignard solution was addedvia cannulation to a solution of picolinaldehyde (2.0 ml, 20.93 mmol) indry THF (55 mL) at 0° C. The reaction mixture was stirred for 5 minutesat 0° C., then warmed to room temperature for 1 hour. The reactionmixture was then cooled in an ice bath and quenched with saturatedaqueous ammonium chloride. The mixture was partitioned between brine andethyl acetate. The separated aqueous phase was further extracted withethyl acetate. The organic phase was dried (Na₂SO₄), filtered, andconcentrated. The crude product was purified by flash columnchromatography (silica gel, 0-5% MeOH-DCM) to provide the title compoundas a white solid.

Intermediate 6: Step b(1-Methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone

A heterogenous mixture of(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol (1.41 g, 7.45 mmol,Intermediate 6: step a) and manganese dioxide (3.24 g, 37.27 mmol) in1,4-dioxane (52 mL) was stirred at 100° C. for 2 hours. The reactionmixture was then allowed to cool to room temperature, filtered throughCelite®, rinsed with DCM, and concentrated to provide the title compoundas an off-white solid.

Intermediate 7: Step a Methyl5-bromo-2-(2-(4-chlorophenoxy)acetamido)benzoate

To a solution of methyl 2-amino-5-bromobenzoate (3.03 mL, 17.4 mmol) inTHF (28 mL) was added 2-(4-chlorophenoxy)acetyl chloride (3.92 g, 19.1mmol) to form a suspension. An additional 30 mL of dichloromethane wasadded. The reaction was then cooled to 0° C. and triethylamine (5.32 mL,38.3 mmol) was added dropwise. The cold bath was removed and thereaction was stirred at room temperature for 2 hours. Analysis showedthe reaction to be incomplete, so additional 2-(4-chlorophenoxy)acetylchloride (0.5 mL, 3.22 mmol) was added and reaction solution was stirredfor 1 hour then transferred to a separatory funnel with dichloromethanedilution. The organic phase was washed with water and saturated aqueousNH₄Cl solution, then dried (MgSO₄), filtered, and concentrated to yieldthe title compound.

Intermediate 7: Step b6-Bromo-3-(4-chlorophenoxy)-4-hydroxyquinolin-2(1H)-one

To a suspension of methyl5-bromo-2-(2-(4-chlorophenoxy)acetamido)benzoate (5.15 g, 12.9 mmol,Intermediate 7: step a) in THF (140 mL) at −78° C. was added potassiumbis(trimethylsilyl)amide (0.5 M in toluene, 76.7 mL, 38.4 mmol) over 4minutes, and the mixture was stirred for 5 minutes. The dry-ice/acetonebath was replaced an with an ice-water bath and the reaction was stirredfor 1.5 hours. The reaction was then quenched with water and ethylacetate was added. The organic layer was removed and the aqueous layerwas acidified with 2 N HCl (kept pH above 2). An off-white precipitateformed which was filtered and the solid was dried overnight in the airto yield the title compound.

Intermediate 7: Step c 6-Bromo-2,4-dichloro-3-(4-chlorophenoxy)quinoline

To a suspension of6-bromo-3-(4-chlorophenoxy)-4-hydroxyquinolin-2(1H)-one (4.59 g, 12.5mmol, Intermediate 7: step b) in acetonitrile (40 mL) was addedphosphorous oxychloride (3.50 mL, 37.6 mmol) and the mixture was heatedto 100° C. for 8 hours. The reaction mixture was cooled and the formedprecipitate was collected by filtration on a Buchner funnel to yield thefirst crop of the title compound. The filtrate was subsequentlyconcentrated to approximately one third of its original volume thencooled to 0° C. and the precipitate was collected on a Buchner funnel toyield a second crop of the title compound.

Intermediate 7: Step d6-Bromo-4-chloro-3-(4-chlorophenoxy)-2-(3-isopropoxyazetidin-1-yl)quinoline

To 6-bromo-2,4-dichloro-3-(4-chlorophenoxy)quinoline (0.50 g, 1.24 mmol,Intermediate 7: step c) was added N,N-dimethylformamide (3 mL) and3-isopropoxyazetidine-HCl (0.188 g, 1.24 mmol), and the reaction washeated at 60° C. overnight. The reaction was cooled, diluted with ethylacetate and the organic layer was washed with water five times to removethe N,N-dimethylformamide. The organic layer was dried (MgSO₄), filteredand concentrated, then purified over a silica gel column with ethylacetate/heptane to afford the title compound.

Intermediate 8: Step a 6-Bromo-4-hydroxyquinolin-2(1H)-one

According to the general method described in Synth. Commun. 2010, 40,732, a mixture of 4-bromoaniline (10.0 g, 58.1 mmol) and2,2-dimethyl-1,3-dioxan-4,6-dione (8.40 g, 58.1 mmol) was heated at 80°C. for 1 hour and cooled to room temperature to receive3-((4-bromophenyl)amino)-3-oxopropanoic acid as a solid. A stream ofnitrogen gas was passed over the solid product to remove liquid acetoneformed as a by-product. To this solid was added Eaton's reagent (40 mL)and the mixture was heated at 70° C. for 12 hours and then cooled toroom temperature. To the resulting mixture was added water and stirredvigorously to receive a suspension which was filtered. The solid residuewas washed with water and dried in air to yield the title compound.

Intermediate 8: Step b(6-Bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)(phenyl)iodoniumtrifluoromethanesulfonate

To a suspension of 6-bromo-4-hydroxyquinolin-2(1H)-one (11.0 g, 45.8mmol, Intermediate 8, step a) and (diacetoxyiodo)benzene (13.4 g, 41.7mmol) in dichloromethane (180 mL) at 0° C. was addedtrifluoromethanesulfonic acid (4.06 mL, 45.8 mmol) dropwise. Theresulting mixture was stirred in an ice-water bath for 1 hour and atroom temperature for 2 hours to receive a suspension which was filtered.The solid product was washed with dichloromethane and dried under vacuumat 50° C. for 12 hours to yield the title compound.

Intermediate 8: Step c6-Bromo-4-hydroxy-3-(phenylamino)quinolin-2(1H)-one

A mixture of(6-bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)(phenyl)iodoniumtrifluoromethanesulfonate (1.40 g, 2.36 mmol, Intermediate 8, step b) and aniline (1 mL)was stirred for 4 hours at room temperature. To this was added DCM andthe resulting suspension was filtered. The solid was washed first withDCM followed by water and air dried under vacuum at 50° C. to yield thetitle compound.

Intermediate 8: Step d 6-Bromo-2,4-dichloro-N-phenylquinolin-3-amine

To 6-bromo-4-hydroxy-3-(phenylamino)quinolin-2(1H)-one (648 mg, 1.96mmol, Intermediate 8, step c) was added phosphoryl trichloride (5 mL,53.7 mmol) and the mixture was heated at 100° C. for 24 hours. Theresulting solution was concentrated in vacuo to remove excess phosphoryltrichloride and the thick liquid that remained was cooled to 4° C. andtreated with aqueous ammonium hydroxide (28-30%) dropwise to bring thesolution pH between 9-10. To this was added water, and the solution washeated at 40° C. for 0.5 hours and the suspension formed was filtered.The solid, the title compound as phosphoryl amide adduct, was suspendedin water, acidified with concentrated aqueous HCl to pH=2 then heated at50° C. overnight and additionally at 90° C. for 3 hours. The resultingmixture was cooled to room temperature, basified with 3 N aqueous NaOHsolution and extracted with EtOAc. The organic phase was separated,dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (silica gel, 10% EtOAc-heptane)to yield the title compound.

Intermediate 8: Step e tert-Butyl(6-bromo-2,4-dichloroquinolin-3-yl)(phenyl)carbamate

To a solution of 6-bromo-2,4-dichloro-N-phenylquinolin-3-amine (226 mg,0.610 mmol, Intermediate 8, step d) in tetrahydrofuran (6 mL) was addeddi-tert-butyl dicarbonate (214 mg, 0.980 mmol),N,N-dimethylpyridin-4-amine (120 mg, 0.980 mmol) and the mixture wasstirred overnight at room temperature. The resulting solution wasdiluted with EtOAc and the organic phase was washed with saturatedaqueous sodium bicarbonate solution followed by brine. The organic phasewas dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (silica gel, 3% EtOAc-heptane)to yield the title compound.

Example 14-((4-chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-2-(2-oxoazetidin-1-yl)quinolin-3-yl)oxy)benzonitrile.TFA

To a flamed dried sealed tube with molecular sieves (33 mg) was added4-((2,4-dichloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)quinolin-3-yl)oxy)benzonitrile(0.049 g, 0.091 mmol, Example 4),tris(dibenzylideneacetone)dipalladium(0) (0.0043 g, 0.0047 mmol),2-azetidinone (0.009 g, 0.132 mmol), cesium carbonate (0.043 g, 0.130mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.0098 g,0.0169 mmol). The flask was covered with a rubber septum and evacuatedwith vacuum, then purged with nitrogen (repeated three times). Then1,4-dioxane (1 mL) was added and the tube was sealed. The reaction wasthen heated at 100° C. overnight. The reaction was then cooled to roomtemperature, diluted with ethyl acetate and filtered through a pad ofCelite®. The Celite® was washed once with methanol and the filtrate wasconcentrated and purified over a silica gel column with 3% methanol indichloromethane, followed by reverse-phase purification withwater/acetonitrile/0.1% TFA to obtain the product as a trifluoroaceticacid salt.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.96 (s, 1H), 8.16 (s, 1H), 8.07 (d,J=9.09 Hz, 1H), 7.78 (dd, J=2.02, 8.59 Hz, 1H), 7.71 (d, J=9.09 Hz, 2H),7.53-7.33 (m, 4H), 7.02 (d, J=9.09 Hz, 2H), 6.94 (s, 1H), 3.90 (t,J=5.05 Hz, 2H), 3.69 (s, 3H), 3.05 (t, 2H); MS m/e 570.2 [M+H]⁺.

Example 2a4-((4-Chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyrrolidin-1-yl)quinolin-3-yl)oxy)benzonitrile

To4-((6-bromo-4-chloro-2-(pyrrolidin-1-yl)quinolin-3-yl)oxy)benzonitrile(0.22 g, 0.52 mmol, Intermediate 3) in THF (3 mL) at −78° C. was addedn-BuLi [1.6 M in hexanes] (0.390 mL, 0.624 mmol) dropwise and stirredfor 5 minutes. To the resulting solution was added(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone(0.159 g, 0.624 mmol, Intermediate 4: step c) in THF (2.2 mL) and thereaction was stirred for 5 min at −78° C. The dry-ice bath was replacedwith wet-ice bath and the reaction was stirred for 30 minutes while itwarmed to 0° C. The reaction was then quenched with water, ethyl acetatewas added and the organic layer was washed with water. The organic phasewas dried (MgSO₄), filtered, concentrated and purified over a silica gelcolumn with dichloromethane/methanol, followed by reverse-phasepurification with water/acetonitrile/0.1% TFA to obtain the product as atrifluoroacetic acid salt. The fractions were combined and concentrated,ethyl acetate was added, followed by saturated aqueous NaHCO₃ solution.The phases were separated and the organic phase was washed with water.The organic phase was dried (MgSO₄), filtered and concentrated to givethe title compound. ¹H NMR (400 MHz, CD₃OD-d₄) δ ppm 9.01 (s, 1H), 8.79(d, J=2.02 Hz, 1H), 8.07 (d, J=8.08 Hz, 1H), 8.00 (bs, 1H), 7.88 (d,J=8.08 Hz, 1H), 7.87-7.77 (m, 1H), 7.73 (d, J=8.08 Hz, 2H), 7.58 (bs,1H), 7.09-6.97 (m, 3H), 3.73-3.68 (m, 7H), 1.96-1.87 (m, 4H); MS m/e605.3 [M+H]⁺.

Example 2a was purified by supercritical fluid chromatography (SFC)(Daicel Chiralpak AD-H, 5 micrometer, UV 254 nm, 50° C., 50 mL/minute)using an isocratic mixture of CO₂/methanol+0.2% isopropylamine: 85/15.The first eluting enantiomer was then further purified over a silica gelcolumn with 8% methanol in dichloromethane, concentrated, dissolved inTHF (6 mL) and 2.2 equivalents of 1M aqueous HCl in diethyl ether wasadded to the solution, then the solution was concentrated and dried invacuo to give Example 2b.HCl, ¹H NMR (400 MHz, CD₃OD) δ ppm 9.01 (s,1H), 8.79 (d, J=2.02 Hz, 1H), 8.15-8.03 (m, 1H), 8.00 (s, 1H), 7.88 (d,J=8.59 Hz, 1H), 7.83 (d, J=9.09 Hz, 1H), 7.73 (d, J=8.59 Hz, 2H), 7.59(d, J=7.07 Hz, 1H), 7.06 (s, 1H), 7.02 (d, J=8.59 Hz, 2H), 3.76-3.63 (m,7H), 1.96-1.86 (m, 4H); MS m/e 605.3 [M+H]⁺. The second elutingenantiomer was then further purified over a silica gel column with 8%methanol in dichloromethane, concentrated, dissolved in THF (6 mL) and2.2 equivalents of 1M aqueous HCl in diethyl ether was added to thesolution, then the solutions were concentrated and dried in vacuo togive Example 2c.HCl. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.03 (s, 1H), 8.79(s, 1H), 8.13-8.02 (m, 2H), 7.95-7.84 (m, 2H), 7.75 (d, J=8.59 Hz, 2H),7.65 (d, J=8.59 Hz, 1H), 7.14-7.00 (m, 3H), 3.80-3.72 (m, 4H), 3.70-3.73(m, 3H), 2.01-1.90 (m, 4H); MS m/e 605.3 [M+H]⁺.

Example 3a(4-Chloro-2-(diethylamino)-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol

A solution of n-BuLi (2.5 M in hexanes, 0.49 mL, 1.2 mmol) was addeddropwise by syringe to a solution of6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (0.500 g, 1.23mmol, Intermediate 5: step d) in dry THF (20.5 mL) in a dry ice-acetonebath. After 1-2 minutes, a solution of(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (230.9 mg, 1.233mmol, Intermediate 6: step b) in dry THF (1.5 mL) was added dropwise.The reaction was stirred for 2 minutes, then moved into an ice bath for7 minutes, and finally allowed to warm to ambient temperature for 1hour. The reaction was quenched with saturated aqueous ammoniumchloride. The mixture was partitioned between water/brine anddichloromethane. The separated aqueous phase was further extracted withdichloromethane. The organic phase was dried (Na₂SO₄), filtered, andconcentrated. The crude product was purified by flash columnchromatography (silica gel, 100% EtOAc), followed by reverse phasechromatography (ACN/H₂0+0.05% TFA). Product fractions were basified withsaturated aqueous sodium bicarbonate and extracted with DCM, beforebeing dried (Na₂SO₄), filtered, and concentrated to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.54 (d, J=3.9 Hz, 1H), 8.05(d, J=1.6 Hz, 1H), 7.84 (dd, J=9.5, 7.7 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H),7.65 (s, 1H), 7.59 (s, 1H), 7.32 (dd, J=14.1, 5.4 Hz, 3H), 7.05 (t,J=7.3 Hz, 1H), 6.93 (s, 1H), 6.79 (d, J=7.8 Hz, 2H), 6.22 (d, J=1.1 Hz,1H), 3.51 (q, J=14.6, 7.3 Hz, 4H), 3.25 (s, 3H), 1.05 (t, J=7.0 Hz, 6H);MS m/e 514.3 [M+H]⁺.

Example 3a was purified by chiral HPLC (ChiralPak OD, 80:20heptane/EtOH) to provide two pure enantiomers. The first elutingenantiomer is Example 3b: ¹H NMR (400 MHz, CDCl₃) δ ppm 8.62 (d, J=4.8Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.74-7.70 (m, 1H), 7.70-7.66 (m, 1H),7.58 (dd, J=8.7, 2.1 Hz, 1H), 7.48 (s, 1H), 7.32-7.21 (m, 3H), 7.06-7.00(m, 1H), 6.80-6.78 (m, 1H), 6.78-6.76 (m, 1H), 6.61 (s, 1H), 6.33 (s,1H), 3.56 (q, J=7.0 Hz, 4H), 3.45 (s, 3H), 1.11 (t, J=7.0 Hz, 6H); MSm/e 514.2 [M+H]⁺. The second eluting enantiomer is Example 3c: ¹H NMR(400 MHz, CDCl₃) δ ppm 8.61 (d, J=4.8 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H),7.74-7.70 (m, 1H), 7.70-7.65 (m, 1H), 7.58 (dd, J=8.8, 2.1 Hz, 1H), 7.51(s, 1H), 7.32-7.21 (m, 3H), 7.02 (t, J=7.4 Hz, 1H), 6.80-6.78 (m, 1H),6.78-6.76 (m, 1H), 6.61 (s, 1H), 6.34 (s, 1H), 3.56 (q, J=7.0 Hz, 4H),3.45 (s, 3H), 1.11 (t, J=7.0 Hz, 6H); MS m/e 514.2 [M+H]⁺.

Example 44-((2,4-Dichloro-6-((4-chlorophenyl)(hydroxy)(l-methyl-1H-imidazol-5-yl)methyl)quinolin-3-yl)oxy)benzonitrile

To 4-((6-bromo-2,4-dichloroquinolin-3-yl)oxy)benzonitrile (0.350 g,0.888 mmol, Intermediate 2: step d) and(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (0.274 g, 1.24mmol, Intermediate 1: step b) was added THF (12 mL) to form a solution.The reaction was cooled to −78° C. and became a white suspension, thenn-BuLi [1.6 M in hexanes] (0.78 mL, 1.2 mmol) was added via a syringe.The reaction was stirred for 15 minutes at −78° C. The dry-ice bath wasthen replaced with a wet-ice bath and stirred for 15 minutes while itwarmed to 0° C. The reaction was then quenched with water, ethyl acetatewas added and the organic layer was washed with water. The organic phasewas dried (MgSO₄), filtered, concentrated, then purified over a silicagel column with 6% methanol in dichloromethane to give the titlecompound. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.26-8.23 (m, 1H), 8.07-8.03 (m,1H), 7.89-7.85 (m, 1H), 7.83-7.82 (m, 2H), 7.76-7.71 (m, 2H), 7.68-7.67(m, 1H), 7.38-7.36 (m, 2H), 7.10-7.05 (m, 2H), 6.34-6.32 (m, 1H), 3.48(s, 3H); MS m/e 535.05 [M+H]⁺.

Example 5a2-(Diethylamino)-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methyl)-3-phenoxyquinoline-4-carbonitrile

(4-Chloro-2-(diethylamino)-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol(170 mg, 0.165 mmol, Example 3a), zinc cyanide (24.5 mg, 0.209 mmol),zinc dust (7.6 mg, 0.116 mmol), X-Phos (9.1 mg, 0.0185 mmol), andPd₂(dba)₃ (16.1 mg, 0.0176 mmol) were charged to an oven-dried microwavevial. The vial was evacuated and back-filled with nitrogen.Dimethylacetamide (1 mL) was sparged with argon and added to the mixturevia syringe. Nitrogen was bubbled through the reaction mixture for 5minutes and the mixture was heated at 120° C. for 4 hours. The mixturewas allowed to cool to ambient temperature, filtered through Celite®,and rinsed with ethyl acetate. The filtrate was concentrated and thecrude product was purified by reverse-phase chromatography(ACN/H₂0+0.05% TFA). Product fractions were basified with saturatedaqueous sodium bicarbonate and extracted with DCM. The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated to provide thetitle compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.64-8.61 (m, 1H), 7.88(d, J=2.0 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.70 (td, J=7.7, 1.7 Hz, 1H),7.64 (dd, J=8.8, 2.1 Hz, 1H), 7.47 (s, 1H), 7.32-7.27 (m, 3H), 7.22 (dt,J=7.9, 1.1 Hz, 1H), 7.11-7.06 (m, 1H), 6.85-6.80 (m, 2H), 6.57 (s, 1H),6.35 (s, 1H), 3.58 (q, J=7.0 Hz, 4H), 3.43 (s, 3H), 1.12 (t, J=7.0 Hz,6H); MS m/e 505.4 [M+H]⁺.

Example 5a was purified by chiral SFC (ChiralPak AD, 75:25 CO₂/iPrOH(+0.6% iPrNH₂)) to provide two pure enantiomers. The first elutingenantiomer was Example 5b: ¹H NMR (400 MHz, CDCl₃) δ ppm 8.64-8.61 (m,1H), 7.88 (d, J=1.9 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71 (td, J=7.7,1.7 Hz, 1H), 7.63 (dd, J=8.8, 2.1 Hz, 1H), 7.48 (s, 1H), 7.33-7.27 (m,3H), 7.22 (d, J=7.9 Hz, 1H), 7.11-7.06 (m, 1H), 6.85-6.81 (m, 2H), 6.58(s, 1H), 6.35 (s, 1H), 3.58 (q, J=7.1 Hz, 4H), 3.43 (s, 3H), 1.12 (t,J=7.0 Hz, 6H); MS m/e 505.3 [M+H]⁺. The second eluting enantiomer wasExample 5c: ¹H NMR (400 MHz, CDCl₃) δ ppm 8.65-8.60 (m, 1H), 7.88 (d,J=1.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71 (td, J=7.7, 1.7 Hz, 1H),7.63 (dd, J=8.8, 2.1 Hz, 1H), 7.48 (s, 1H), 7.33-7.27 (m, 3H), 7.22 (d,J=7.9 Hz, 1H), 7.11-7.06 (m, 1H), 6.85-6.81 (m, 2H), 6.58 (s, 1H), 6.35(s, 1H), 3.58 (q, J=7.1 Hz, 4H), 3.43 (s, 3H), 1.12 (t, J=7.0 Hz, 6H);MS m/e 505.3 [M+H]⁺.

Example 6(4-Chloro-3-(4-chlorophenoxy)-2-(3-isopropoxyazetidin-1-yl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

To6-bromo-4-chloro-3-(4-chlorophenoxy)-2-(3-isopropoxyazetidin-1-yl)quinoline(0.35 g, 0.72 mmol, Intermediate 7: step d) in THF (7 mL) at −78° C. wasadded n-BuLi (1.6 M in hexanes, 0.58 mL, 0.93 mmol) dropwise and stirredfor 5 minutes. To the resulting solution was added(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone(0.22 g, 0.86 mmol, Intermediate 4: step c) and the reaction was stirredfor 5 min at −78° C. The dry-ice bath was replaced with an ice-waterbath and the reaction was stirred for 30 minutes at 0° C. Contents werethen re-cooled to −78° C. and additional n-BuLi (1.6 M in hexanes, 0.58mL, 0.93 mmol and(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone(0.22 g, 0.86 mmol, Intermediate 4: step c) were added and the reactionstirred for 5 minutes. The dry-ice bath was replaced with an ice-waterbath and the reaction was stirred for an additional 30 minutes at 0° C.then quenched with water. The reaction solution was transferred to aseparatory funnel with ethyl acetate dilution, washed with water,separated, dried (MgSO₄), filtered and concentrated. The crude productwas purified by flash column chromatography withdichloromethane/methanol, followed by reverse-phase purification withwater/acetonitrile/0.1% TFA to obtain the product as a trifluoroaceticacid salt. The fractions containing the desired product were combinedand concentrated, then re-dissolved in ethyl acetate and washed with asaturated aqueous NaHCO₃ solution and water. The organic phase was dried(MgSO₄), filtered and concentrated to give the title compound. ¹H NMR(400 MHz, CD₃OD) δ ppm 8.76 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.3, 2.3 Hz,1H), 7.96 (d, J=2.2 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.9 Hz,1H), 7.72 (s, 1H), 7.57 (dd, J=8.9, 2.2 Hz, 1H), 7.37-7.28 (m, 2H),6.86-6.79 (m, 2H), 6.34 (s, 1H), 4.48-4.35 (m, 3H), 4.05-3.97 (m, 2H),3.69-3.59 (m, 1H), 3.48 (s, 3H), 1.12 (d, J=6.1 Hz, 6H); MS m/e 658.2[M+H]⁺.

Example 7 tert-Butyl(2,4-dichloro-6-((3-chlorophenyl)(hydroxy)(pyridin-3-yl)methyl)quinolin-3-yl)(phenyl)carbamate

To a solution of tert-butyl(6-bromo-2,4-dichloroquinolin-3-yl)(phenyl)carbamate (60 mg, 0.13 mmol,Intermediate 8, step e) and (3-chlorophenyl)(pyridin-3-yl)methanone (31mg, 0.14 mmol) in tetrahydrofuran (1 mL) at −78° C. was addedn-butyllithium (1.6 M solution in hexanes, 0.10 mL, 0.17 mmol) dropwiseand stirred at this temperature for 10 minutes then at room temperaturefor 2 hours. Analysis showed the reaction to be incomplete and henceadditional aliquots of reagents were added. The resulting solution wascooled back to −78° C. and treated with(3-chlorophenyl)(pyridin-3-yl)methanone (10 mg, 0.05 mmol) andn-butyllithium (1.6 M solution in hexanes, 0.050 mL, 0.080 mmol) dropwise and stirred at this temperature for 1 hour and then allowed to warmand stir at room temperature overnight. Analysis showed the reaction tobe incomplete and hence additional aliquots of reagents were addedagain. The reaction solution was cooled back to −78° C. and treated withn-butyllithium (1.6 M solution in hexanes, 0.10 mL, 0.16 mmol) drop wiseand stirred at this temperature for 4 hours. Analysis showed thereaction to be incomplete and hence additional aliquots of reagents wereagain to push the reaction to completion. The reaction solution wastreated with (3-chlorophenyl)(pyridin-3-yl)methanone (20 mg, 0.09 mmol)and n-butyllithium (1.6 M solution in hexanes, 0.10 mL, 0.16 mmol) dropwise and stirred at this temperature for 3 hours. The resulting solutionwas quenched with water and diluted with EtOAc. The organic phase wasseparated, dried (MgSO₄), filtered and concentrated. The residue waspurified by flash column chromatography (silica gel, 50% EtOAc-heptane)to yield the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.58 (s, 2H),8.16 (d, J=2.1 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.75-7.62 (m, 2H),7.38-7.28 (m, 8H), 7.16 (t, J=4.9 Hz, 2H), 1.43 (s, 9H); MS m/e 607.1[M+H]⁺.

In Vitro Biological Data ThermoFluor® Assay

ThermoFluor® is a fluorescence based assay that estimates ligand bindingaffinities by measuring the effect of a ligand on protein thermalstability (Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D.,Lobanov, V. S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B.A., Lane, P., and Salemme, F. R. (2001) High-density miniaturizedthermal shift assays as a general strategy for drug discovery. J BiomolScreen 6, 429-40, and Matulis, D., Kranz, J. K., Salemme, F. R., andTodd, M. J. (2005) Thermodynamic stability of carbonic anhydrase:measurements of binding affinity and stoichiometry using ThermoFluor.Biochemistry 44, 5258-66). This approach is applicable to a wide varietyof systems, and rigorous in theoretical interpretation throughquantitation of equilibrium binding constants (K_(D)).

In a ThermoFluor® experiment where protein stability is monitored as thetemperature is steadily increased, an equilibrium binding ligand causesthe midpoint of an unfolding transition (T_(m)) to occur at a highertemperature. The shift in the melting point described as a ΔT_(m) isproportional to the concentration and affinity of the ligand. Thecompound potency may be compared as a rank order of either ΔT_(m) valuesat a single compound concentration or in terms of K_(D) values,estimated from concentration response curves.

RORγt ThermoFluor® Assay Construct

For the RORγt construct used in the ThermoFluor® assay, numbering forthe nucleotide sequences was based on the reference sequence for humanRORγt, transcript variant 2, NCBI Accession: NM_001001523.1 (SEQ IDNO:1). Nucleotides 850-1635 (SEQ ID NO:2) coding for the wild type humanRORγt ligand binding domain (RORγt LBD) were cloned into the pHIS1vector, a modified pET E. coli expression vector (Accelagen, San Diego),containing an in-frame N-terminal His-tag and a TurboTEV proteasecleavage site (ENLYFQG, SEQ ID NO:3) upstream of the cloned insertsequence. The amino acid sequence for the RORγt construct used in theThermofluor assay is shown as SEQ ID NO:4.

ThermoFluor® experiments were carried out using instruments owned byJanssen Research and Discovery, L.L.C. through its acquisition of3-Dimensional Pharmaceuticals, Inc. 1,8-ANS (Invitrogen) was used as afluorescent dye. Protein and compound solutions are dispensed into black384-well polypropylene PCR microplates (Abgene) and overlayed withsilicone oil (1 μL, Fluka, type DC 200) to prevent evaporation.

Bar-coded assay plates are robotically loaded onto a thermostaticallycontrolled PCR-type thermal block and then heated at a typical ramp-rateof 1° C./min for all experiments. Fluorescence was measured bycontinuous illumination with UV light (Hamamatsu LC6) supplied via fiberoptic and filtered through a band-pass filter (380-400 nm; >6 ODcutoff). Fluorescence emission of the entire 384-well plate was detectedby measuring light intensity using a CCD camera (Sensys, RoperScientific) filtered to detect 500±25 nm, resulting in simultaneous andindependent readings of all 384 wells. Images were collected at eachtemperature, and the sum of the pixel intensity in a given area of theassay plate was recorded versus temperature. Reference wells containedRORγt without compounds, and the assay conditions were as follows:

-   -   0.065 mg/mL RORγt    -   60 μM 1,8-ANS    -   100 mM Hepes, pH 7.0    -   10 mM NaCl    -   2.5 mM GSH    -   0.002% Tween-20

Project compounds were arranged in a pre-dosed mother plate (GreinerBio-one) wherein compounds are serially diluted in 100% DMSO by 1:2 froma high concentration of 10 mM over 12 columns within a series (column 12is a reference well containing DMSO, no compound). The compounds wererobotically dispensed directly into assay plates (1×=46 nL) using aHummingbird capillary liquid handling instrument (Digilab). Followingcompound dispense, protein and dye in buffer was added to achieve thefinal assay volume of 3 μL, followed by 1 μL of silicone oil.

The binding affinity was estimated as described previously (Matulis, D.,Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005) Thermodynamicstability of carbonic anhydrase: measurements of binding affinity andstoichiometry using ThermoFluor®. Biochemistry 44, 5258-66) using thefollowing thermodynamic parameters of protein unfolding:

Reference RORγt T_(m): 47.8° C.

ΔH_((Tm))=115 kcal/molΔC_(p(Tm))=3 kcal/mol

Cell Based Biological Data RORγt Reporter Assay

A reporter assay was used to test functional activity of RORγtmodulatory compounds on transcriptional activation driven by the RORγtLBD. Cells used in the assay were co-transfected with two constructs.The first construct, pBIND-RORγt LBD, contained the wild type humanRORγt LBD fused to the DNA binding domain of the GAL4 protein. Thesecond construct, pGL4.31 (Promega Cat no. C935A), contained multipleGAL4 responsive DNA elements upstream of firefly luciferase. To generatea background control, cells were similarly co-transfected with twoconstructs, but in the first construct the AF2 amino acid motif in theRORγt LBD was changed from LYKELF (SEQ ID NO:5) to LFKELF (SEQ ID NO:6).The AF2 mutation has been shown to prevent co-activator binding to theRORγt LBD, thus preventing transcription of firefly luciferase. Themutant construct was called pBIND-RORγt-AF2.

For the RORγt constructs used in the reporter assay, numbering for thenucleotide sequences was also based on the reference sequence for humanRORγt, transcript variant 2, NCBI Accession: NM 001001523.1 (SEQ IDNO:1). For the wild type human RORγt LBD construct, pBIND-RORγt LBD,nucleotides 850-1635 (SEQ ID NO:2) coding for the wild type human RORγtLBD were cloned into EcoRI and NotI sites in the pBIND vector (Promegacat. No E245A). The pBIND vector contains the GAL4 DNA Binding Domain(GAL4 DBD) and the renilla luciferase gene under control of the SV40promoter. Renilla luciferase expression serves as a control fortransfection efficiency and cell viability. For the background controlconstruct, pBIND-RORγt-AF2, the AF2 domain of RORγt LBD was mutatedusing the Quik Change II Site Directed Mutagenesis System (StratageneCat. No. 200519). The nucleotide sequence coding for the RORγt LBDsequence with the mutated AF2 domain is shown as SEQ ID NO:7. The aminoacid sequences for the wild type RORγt LBD and RORγt LBD with themutated AF2 domain are shown as SEQ ID NO:8 and SEQ ID NO:9,respectively.

The reporter assay was performed by transiently transfecting HEK293Tcells with 5 μg of pBIND-RORγt LBD or pBIND-RORγt LBD-AF2 and 5 μgpGL4.31 (Promega Cat no. C935A) using Fugene 6 (Invitrogen Cat no.E2691) at a 1:6 ratio of DNA:Fugene 6 in a T-75 flask in which cellswere at least 80% confluent. Twenty four hours after bulk transfection,cells were plated into 96-well plates at 50,000 cells/well in phenol-redfree DMEM containing 5% Lipid Reduced FCS and Pen/Strep. Six hours afterplating, cells were treated with compounds for 24 hours. Media wasremoved and cells were lysed with 50 μL 1× Glo Lysis Buffer (Promega).Dual Glo Luciferase Reagent (50 μL/well) was then added and fireflyluciferase luminescence was read on an Envision after a ten minuteincubation. Finally, Stop and Glo reagent (50 μL/well) was added andrenilla luciferase luminescence was read on an Envision after a tenminute incubation. To calculate the effect of compounds on RORγtactivity, the ratio of firefly to renilla luciferase was determined andplotted against compound concentration. Agonist compounds increaseRORγt-driven luciferase expression, and antagonist or inverse agonistcompounds decrease luciferase expression.

Human Th17 Assay

The human Th17 assay tests the effect of RORγt modulatory compounds onIL-17 production by CD4 T cells under conditions which favor Th17differentiation.

Total CD4⁺ T cells were isolated from the peripheral blood mononuclearcells (PBMC) of healthy donors using a CD4⁺ T cell isolation kit II,following the manufacturer's instructions (Miltenyi Biotec). Cells wereresuspended in a medium of RPMI-1640 supplemented with 10% fetal bovineserum, penicillin, streptomycin, glutamate, and β-mercaptoethanol andwere added to 96-well plates at 1.5×10⁵ per 100 μL per well. 50 μL ofcompound at titrated concentrations in DMSO were added into each well atfinal DMSO concentration at 0.2%. Cells were incubated for 1 hour, then50 μL of Th17 cell differentiation medium was added to each well. Thefinal concentrations of antibodies and cytokines (R&D Systems) indifferentiation medium were: 3×10⁶/mL anti-CD3/CD28 beads (preparedusing human T cell activation/expansion kit, Miltenyi Biotec), 10 μg/mLanti-IL4, 10 μg/mL anti-IFNγ, 10 ng/mL IL1β, 10 ng/mL IL23, 50 ng/mLIL6, 3 ng/mL TGFβ and 20 U/mL IL2. Cells were cultured at 37° C. and 5%CO₂ for 3 days. Supernatants were collected and the accumulated IL-17 inculture was measured by using MULTI-SPOT® Cytokine Plate followingmanufacture's instruction (Meso Scale Discovery). The plate was readusing Sector Imager 6000, and IL-17 concentration was extrapolated fromthe standard curve. The IC50s were determined by GraphPad.

TABLE 1 RORγt RORγt reporter ThermoFluor ® reporter Assay, Human ExampleAssay, Kd Assay, % inhibition Th17 Assay, Number (μM) IC50 (μM) @ 6 μMIC₅₀ (μM) 1 0.058 0.18 101 0.3 2a 0.066 0.28 99 0.088 2b 0.15 0.29 970.32 2c 0.022 0.046 96 0.1 3a ND ND ND ND 3b 0.14 0.2 101 0.18 3c 0.461.1 101 ND 4 ND ND ND ND 5a ND ND ND ND 5b ND 0.87 102 ND 5c >63 0.27103 0.15 6 11 >6 41 ND 7 23 1.4 72 ND All data shown in Table 1 iseither the value of one data point or the average of more than one datapoint. ND—no data.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

All documents cited herein are incorporated by reference.

What is claimed is:
 1. A method for treating or ameliorating a RORγtmediated inflammatory syndrome, disorder or disease comprisingadministering to a subject in need thereof an effective amount of acompound of Formula I

wherein: R¹ is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl,piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl,thiophenyl, benzoxazolyl, or quinolinyl; wherein said piperidinyl,pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolyl,and pyrazolyl are optionally substituted with SO₂CH₃, C(O)CH₃, C(O)NH₂,CH₃, CH₂CH₃, CF₃, Cl, F, —CN, OCH₃, N(CH₃)₂, —(CH₂)₃OCH₃, SCH₃, OH,CO₂H, CO₂C(CH₃)₃, or OCH₂OCH₃; and optionally substituted with up to twoadditional substituents independently selected from the group consistingof Cl, OCH₃, and CH₃; and wherein said triazolyl, oxazolyl, isoxazolyl,and thiazolyl are optionally substituted with one or two CH₃ groups; andwherein said azetidinyl is optionally substituted with CO₂C(CH₃)₃,C(O)NH₂, CH₃, SO₂CH₃, or C(O)CH₃; R² is 1-methyl-1,2,3-triazolyl,pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl,pyridazyl, pyrazin-2-yl, oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl,N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl,N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, N-acetylpiperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl,N—C₍₁₋₂₎alkyl-piperidinyl, thiazol-5-yl,1-(3-methoxypropyl)-imidazol-5-yl, or 1-C₍₁₋₂₎alkyl imidazol-5-yl;wherein said 1-C₍₁₋₂₎alkyl imidazol-5-yl is optionally substituted withup to two additional CH₃ groups, or one substituent selected from thegroup consisting of SCH₃, and Cl; and said pyridyl, and pyridyl-N-oxideare optionally substituted with up to two substituents independentlyselected from the group consisting of C(O)NH₂, —CN, OCH₃, CF₃, Cl, andCH₃; and said thiazol-5-yl, oxazolyl, and isoxazolyl are optionallysubstituted with up to two CH₃ groups; and said 1-methyl pyrazol-4-yl isoptionally substituted with up to two additional CH₃ groups; R³ is H,OH, OCH₃, NHCH₃, N(CH₃)₂ or NH₂; R⁴ is H, or F; R⁵ is H, Cl, —CN, CF₃,SCH₃, OC₍₁₋₃₎alkyl, OH, C₍₁₋₄₎alkyl, N(CH₃)OCH₃, NH(C₍₁₋₂₎alkyl),N(C₍₁₋₂₎alkyl)₂, NH-cyclopropyl, OCHF₂, 4-hydroxy-piperidinyl,azetidin-1-yl, or fur-2-yl; R⁶ is —O-phenyl, —NHphenyl,—N(C₍₁₋₃₎alkyl)phenyl, —N(CO₂C(CH₃)₃)phenyl, —O-pyridyl, —NHpyridyl,—N(C₍₁₋₃₎alkyl)pyridyl, or —N(CO₂C(CH₃)₃)pyridyl wherein said phenylportions thereof or said pyridyl portions thereof are optionallysubstituted with OCF₃, SO₂CH₃, CF₃, CHF₂, imidazol-1-yl, pyrazol-1-yl,1,2,4-triazol-1-yl, CH₃, OCH₃, Cl, F, or —CN; R⁷ is H, Cl, —CN,C₍₁₋₄₎alkyl, OCH₂CF₃, OCH₂CH₂OCH₃, CF₃, SCH₃, SO₂CH₃, OCHF₂, NA¹A²,C(O)NHCH₃, N(CH₃)CH₂CH₂NA¹A², OCH₂CH₂NA¹A², OC₍₁₋₃₎alkyl,OCH₂-(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl, pyrazol-4-yl,pyrid-3-yl, or pyrimidin-5-yl; thiophen-3-yl, 1-methyl-indazol-5-yl,1-methyl-indazol-6-yl, phenyl, or

 wherein said imidazolyl or pyrazolyl can be optionally substituted witha CH₃ group; A¹ is H or C₍₁₋₄₎alkyl; A² is H, C₍₁₋₄₎alkyl, cyclopropyl,C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH, C(O)C₍₁₋₂₎alkyl, or OCH₃; or A¹and A² may be taken together with their attached nitrogen to form a ringselected from the group consisting of:

R_(a) is H, F, OC₍₁₋₃₎alkyl, or OH; R_(b) is CH₃, or phenyl; R⁸ is H,CH₃, OCH₃, or F; R⁹ is H, or F; and pharmaceutically acceptable saltsthereof.
 2. The method of claim 1, wherein the disease is selected fromthe group consisting of: inflammatory bowel diseases, rheumatoidarthritis, psoriasis, chronic obstructive pulmonary disorder, psoriaticarthritis, ankylosing spondylitis, neutrophilic asthma, steroidresistant asthma, multiple sclerosis, and systemic lupus erythematosus.3. The method of claim 2, wherein the disease is psoriasis.
 4. Themethod of claim 2, wherein the disease is rheumatoid arthritis.
 5. Themethod of claim 2, wherein the inflammatory bowel disease is ulcerativecolitis.
 6. The method of claim 2, wherein the inflammatory boweldisease is Crohn's disease.
 7. The method of claim 2, wherein thedisease is multiple sclerosis.
 8. The method of claim 2, wherein thedisease is neutrophilic asthma.
 9. The method of claim 2, wherein thedisease is steroid resistant asthma.
 10. The method of claim 2, whereinthe disease is psoriatic arthritis.
 11. The method of claim 2, whereinthe disease is ankylosing spondylitis.
 12. The method of claim 2,wherein the disease is systemic lupus erythematosus.
 13. The method ofclaim 2, wherein the disease is chronic obstructive pulmonary disorder.14. A method of treating or ameliorating a syndrome, disorder ordisease, in a subject in need thereof comprising administering to thesubject an effective amount of a compound of claim 1 or composition ormedicament thereof in a combination therapy with one or moreanti-inflammatory agents, or immunosuppressive agents, wherein saidsyndrome, disorder or disease is selected from the group consisting of:rheumatoid arthritis, and psoriasis.
 15. A method of claim 1 wherein thecompound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 16. The method of claim15, wherein the disease is selected from the group consisting of:inflammatory bowel diseases, rheumatoid arthritis, psoriasis, chronicobstructive pulmonary disorder, psoriatic arthritis, ankylosingspondylitis, neutrophilic asthma, steroid resistant asthma, multiplesclerosis, and systemic lupus erythematosus.
 17. The method of claim 16,wherein the disease is psoriasis.
 18. The method of claim 16, whereinthe disease is rheumatoid arthritis.
 19. The method of claim 16, whereinthe inflammatory bowel disease is ulcerative colitis.
 20. The method ofclaim 16, wherein the inflammatory bowel disease is Crohn's disease. 21.The method of claim 16, wherein the disease is multiple sclerosis. 22.The method of claim 16, wherein the disease is neutrophilic asthma. 23.The method of claim 16, wherein the disease is steroid resistant asthma.24. The method of claim 16, wherein the disease is psoriatic arthritis.25. The method of claim 16, wherein the disease is ankylosingspondylitis.
 26. The method of claim 16, wherein the disease is systemiclupus erythematosus.
 27. The method of claim 16, wherein the disease ischronic obstructive pulmonary disorder.
 28. A method of treating orameliorating a syndrome, disorder or disease, in a subject in needthereof comprising administering to the subject an effective amount of acompound of claim 15 or composition or medicament thereof in acombination therapy with one or more anti-inflammatory agents, orimmunosuppressive agents, wherein said syndrome, disorder or disease isselected from the group consisting of: rheumatoid arthritis, andpsoriasis.